Method for noninvasive continuous determination of physiologic characteristics

ABSTRACT

The invention comprises methods for noninvasively monitoring physiological characteristics of a patient&#39;s blood. Determinations of blood constituent concentrations may be made by comparing absorbance of radiation at varying parameters, such as path length and blood pressure. Preferably, changes in pressure are effected by changing the height of the probes relative to the patient&#39;s heart. Determinations of blood pH may be made by comparing absorbance of the blood at different wavelengths. The temperature of the blood, and thus of the patient&#39;s core, may also be accurately determined. Further, cardiac output characteristics and blood pressures may be noninvasively determined using the methods of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/912,721, filed Aug. 4, 2004, which is a division of U.S. applicationSer. No. 10/008,245, filed Nov. 7, 2001, now U.S. Pat. No. 6,819,950,which is a continuation of U.S. application Ser. No. 09/684,104, filedOct. 6, 2000, now U.S. Pat. No. 6,537,225.

FIELD OF THE INVENTION

The present invention relates generally to noninvasive methods ofquantitatively determining various physiologic parameters relating tocardiovascular and respiratory function. More particularly, theinvention relates to methods and devices for continuous, noninvasivedetermination of: hemoglobin, glucose and other blood constituentconcentrations, blood pH and acid-base balance, blood flowdifferentials, blood temperature, arterial blood pressure, venouspressure, arterial oxygen saturation, venous oxygen saturation, arterialpulse wave velocity, aortic pulse wave velocity, aortic pulse flowvelocity, cardiac stroke volume, cardiac index, cardiac output, heartrate, respiratory rate and cardiac ejection fraction.

BACKGROUND OF THE INVENTION

Critically ill and seriously injured patients require constant care andattention. Doctors, nurses, and hospital technicians need a continuousflow of information about the many patients under their care. Heart rateand blood pressure measurements are two primary vital signs thatindicate the health of patients under their care. When these two commonindices of wellness fall below normal readings, a patient is usually indistress and requires immediate attention.

Dangerous conditions brought about by a cardio-vascular or pulmonarydisease, severe trauma, or drug abuse may bring about a failure of thelungs and heart to supply the bloodstream with life-giving oxygen. Sucha fatal deficiency can be detected by continually gauging the amount ofhemoglobin in the bloodstream that is carrying oxygen. This third vitalsign, which manifests oxygen saturation of the blood, is especiallycritical because a rapid decline in oxygen in the bloodstream isassociated with increased risk of patient mortality.

It is well known that blood pressure can be directly measured by placinga fluid-filled catheter directly into the vessel and coupling this to anelectro-mechanical transducer. This is the most accurate means, but hasall the disadvantages of invasive measurement, including pain oninsertion, risk of infection or disease transmission, risk of bleedingor thrombosis, and great expense. A further disadvantage is the creationof toxic medical waste (needle, gloves, skin dressing, etc).

Blood pressure measurement can also be measured indirectly using anocclusive cuff (with either auscultation or oscillometry to make thedetermination). This is the most common means of blood pressuremeasurement. Illustrative is U.S. Pat. Nos. 5,582,179, 5,048,533,5,152,296 and 4,793,360.

A further occlusive cuff apparatus is disclosed in U.S. Pat. No.5,766,130. According to the invention, the apparatus includes multiple“pressurized pneumatic cuffs” that are used to “plot blood pressureand/or volumetric blood flow wave forms from a plurality of separatedigits and/or extremities of a patient so that circulatory parametersmay be measured rapidly and recorded from a great number of thepatient's digits or limbs”.

Although commonly employed, the occlusive cuff also has numerousdisadvantages, which include discomfort, intermittent readings, and poorreliability.

An additional means of determining blood pressure is through anassessment of “pulse wave velocity”. Several prior art referencesdisclose methods and/or apparatus employing such means. Illustrative isU.S. Pat. No. 5,649,543.

There are also several prior art references that disclose methods and/orapparatus for determining blood pressure through a “pulse waveamplitude” assessment. Illustrative are U.S. Pat. Nos. 4,735,213,4,872,461, 4,793,360, 5,265,011, 5,385,149, 5,511,303, 5,582,179,5,680,867 and 5,882,311.

Additional physiologic characteristics such as blood temperature and pHprovide further information regarding the status of the patient.Moreover, combinations of measurements can be used to determine specificcardio-pulmonary parameters.

Acid-base balance (the most common measure is pH) is perhaps the mostimportant factor in the chemistry of both biologic and non-biologicsystems. It figures in speed of reactions; indeed, if a reaction willoccur at all. In most biologic systems, determination of pH requireslaboratory analysis. The monetary costs are high, and procedures involverisk for patient subject and laboratory technicians among others. Toxicmedical waste (syringes, gloves, etc.) is created and must be disposedof safely. In other systems (and to some extent in biologic systems), pHmeasurement is done in one of two common ways: colorimetric andelectrochemical. Noninvasive measurement of arterial blood pH isdescribed in U.S. Pat. No. 5,978,691.

Although most of the noted noninvasive monitoring methods and apparatus,particularly the occlusive cuff, have been employed for many years byhealth care personnel, the conventional methods and apparatus have onemajor, common drawback—the need for separate calibration.

Accordingly, there is a need for noninvasive methods and devices capableof continuously determining various physiological characteristics, suchas blood pressure, central venous pressure and cardiac output, withoutseparate calibration. There is also a similar need for noninvasivemethods and devices for determining various blood parameters includinghemoglobin, glucose and other blood constituent concentrations, blood pHand acid-base balance, blood flow differentials, blood temperature,blood pressures and pressure wave differentials. As will be appreciatedby one having ordinary skill in the art, the present invention satisfiesthese and other needs.

SUMMARY OF THE INVENTION

The invention comprises methods for noninvasively determining theconcentration of a blood constituent, generally including the steps ofproviding a tissue probe having a radiation emitter with a wavelengthand a detector configured to receive the wavelength after absorbancethrough a path length of the patient's blood; measuring absorbance ofthe patient's blood by emitting and detecting radiation after passagethrough the patient's blood; varying the path length of to providemultiples of path length; measuring absorbance of the patient's blood ateach multiple of the path length; and determining the concentration ofthe blood constituent based upon the changing absorbance. Preferably,the determination is made continuously. The determination can also bemade using calculated multiples of the path length.

Alternatively, the invention comprises the steps of providing a firstand second tissue probe each having a radiation emitter with awavelength and a radiation detector configured to receive the wavelengthafter absorbance through a path length of the patient's blood at aposition relative to the heart of the patient; measuring absorbance ofthe patient's blood by emitting radiation and detecting radiation afterpassage through a first path length of the patient's blood; varying thepressure of the blood within the first and second probes; measuringabsorbance of the blood as the pressure is varied; and computing thetime of arrival and amplitude of the pulse based on the absorbance atthe varying pressures. Preferably, the pressure of the blood within theprobes can be varied by changing the hydrostatic pressure relative tothe heart such as by changing the height of the probe.

These techniques can be applied to arterial or venous blood. Preferably,the blood constituent being measured comprises hemoglobin. By measuringhemoglobin oxygen saturation or blood pH at different probe locations,blood corresponding to a single flow wave can be identified. Bycomparing the timing of the flow wave arrival at the different probelocations, multiple determinations of cardiac characteristics can bemade, including arterial pulse wave velocity, aortic pulse wavevelocity, aortic pulse flow velocity, cardiac stroke volume, cardiacindex, cardiac output, heart rate, respiratory rate and cardiac ejectionfraction. In other embodiments, tissue probes having more than oneradiation emitter and detector pairs can be employed.

The invention also comprises methods for noninvasively determining thepH of blood of a patient, generally including the steps of providing afirst tissue probe having a first and second radiation emitter with afirst and second wavelength, respectively, and a first and secondradiation detector configured to receive the first and secondwavelength, respectively, after absorbance through the patient's blood;measuring absorbance of the patient's blood by emitting radiation at thefirst and second wavelength through the patient's blood and detectingthe radiation after passage through the patient's blood; and computingthe pH of the blood based upon the measured absorbance at the first andsecond wavelengths. The first and second wavelengths are selected sothat the absorbance of the first wavelength depends upon the pH of theblood and the absorbance of the second wavelength is substantiallyindependent of the pH of the blood. Preferably, the method is tailoredto measuring the absorbance spectrum of hemoglobin species that havecertain pH dependent absorption peaks. Since pH is also dependant upontemperature, more accurate results can be obtained if the bloodtemperature is varied. Alternatively, if the pH of the blood ischaracterized, the temperature of the blood can accurately bedetermined.

Yet another embodiment of the invention is a method for non-invasivelydetermining the concentration of a blood constituent comprising thesteps of measuring absorbance of arterial and venous blood; determiningarterial and venous oxygen saturation; subtracting hemoglobin absorbancebased upon the arterial and venous saturation; and determining theconcentration of a blood constituent based upon remaining absorbance.Preferably, the blood constituent comprises glucose.

The invention also includes a device for the noninvasive monitoring of aphysiologic characteristic of a patient's blood. In one embodiment, thedevice comprises a tissue probe having a radiation emitter and aradiation detector configured to receive the radiation after absorbancethrough the patient's blood; a position sensor for determining therelative height of the probe compared to a level corresponding to thepatient's heart; and a controller for computing the physiologiccharacteristic of the patient's blood based on the absorbance of thefirst wavelength of radiation and the relative height of the probe. Theradiation emitters of the invention can utilize a single wavelength or aplurality of discrete wavelengths and may include visible light,infrared light, and ultraviolet light. The probes are adapted for usewith hands, fingers, feet, toes, ears, earlobes, nares, lips, tongue andthe like. Additional radiation emitters and detectors may also be used.Preferably, the probe further comprises ECG leads.

An alternative embodiment of the device of the invention comprises atissue probe and controller in conjunction with a movement generator forinducing a position change of the probe with respect to a levelcorresponding to the patient's heart. Preferably, the movement generatorinduces a known position change of the probe and moves the probe topositions above and below a level corresponding to the patient's heart.

The invention also comprises methods for determining other physiologicalcharacteristics of a patient's blood noninvasively. In one embodiment,absorbance characteristics of the blood are measured at varyingpositions relatively to the level of the patient's heart. By comparingblood parameters such as pulse amplitude, pulse velocity, pulse delay,pulse contour, flow velocity and flow delay to hydrostatic pressuredifferences induced by the position changes, characteristics such asarterial and central venous blood pressure and cardiac output can bedetermined. Alternatively, two probes are used to compute pulse delaysbetween coupled tissues or opposing tissues.

The subject invention relates novel methods for noninvasivedetermination of physiologic characteristics. The first new and uniquemethod and device utilizes changes in hydrostatic pressure induced bypositional changes to facilitate measurements. A second new and uniquemethod and device for noninvasive determination of cardiac output bymeasuring delays in pulse arrival times in coupled organs or members onopposite sides of the body is also described. The two methods are suchthat they can advantageously be used together.

By varying the hydrostatic pressure in an extremity, one can not onlyperform self-calibration for a blood pressure determination, but alsochange the pulse wave velocity and pulse propagation delay with respectto the opposite extremity. With this information, pulse wave velocity,and consequently flow wave velocity at the aortic root can bedetermined.

Similar techniques of varying hydrostatic pressure can be used to assessvenous pressure and saturation. The technique of repetitiousdeterminations made while altering position or other variables allows amultitude of additional analyses to be made. The determinations can bemade intermittently or continuously.

Further objects of the invention are exemplified by the followingpotential applications:

(A-1). A patient is anesthetized for a surgical procedure. Probes areattached to the index fingers of each hand, and a movement generator isplaced on one arm. A complete set of vital signs and physiologiccharacteristics is generated continuously, including: arterial bloodpressure, venous pressure, arterial oxygen saturation, venous oxygensaturation, arterial pulse wave velocity, aortic pulse wave velocity,aortic pulse flow velocity, cardiac stroke volume, cardiac output, heartrate, and respiratory rate. Other characteristics can be calculated ifdesired.(A-2). A patient is anesthetized for a cardiac surgical procedure. Asaccess to the arms is difficult, probes are attached to the patient'stemples. A complete set of vital signs and physiologic characteristicsis continuously generated.(A-3). A patient is anesthetized for a cardiac surgical procedure; thistime the procedure includes valvular repair or replacement. Since thecardiac output and other characteristics can be continuously computed,the adequacy of the surgical repair can be judged immediately.(A-4). As the number of endoscopic or minimally invasive cardiacsurgical procedures is expected to increase, the demand for lessinvasive monitoring will also increase. The device described hereinprovides noninvasive, continuous monitoring of essentially allcardiovascular characteristics.(A-5). Cardiac catheterization procedures are often done on criticallyill patients. As the procedures are usually relatively brief andaccomplished without general anesthesia, invasive monitoring methods areoften not desired despite the illness of the patients. The devicedescribed herein will provide the necessary monitoring that is typicallyprovided by much more invasive, expensive, and time consuming monitors.(A-6). A patient is hospitalized in the intensive care unit of ahospital after a heart attack. Probes are attached to the index fingersof each hand, and a movement generator is placed on an arm or a leg. Acomplete set of vital signs and physiologic characteristics can becontinuously generated. In addition, arrhythmias can be detected anddiagnosed.(A-7). The patient noted above is now moved to a “step-down” ortelemetry unit from the intensive care unit. Because the devicedescribed herein eliminates the need for invasive monitoring lines, acomplete set of vital signs and physiologic characteristics can still becontinuously generated. As the patient has mobility of arms and legs, amovement generator is no longer needed, as the patient's spontaneousmotion, even during sleep, will generate hydrostatic pressures in thelimbs, allowing all computations to be made. In addition, the probes maybe made wireless, and connected to a central nursing station by means ofinfrared or radio frequency communication.(A-8). The patient noted in applications 6 and 7 above is now moved to aregular hospital bed, and does not require continuous monitoring.However, vital signs can still be recorded by a technician moving thedevice from bedside to bedside on a cart. The device does not requirehighly trained nursing personnel to operate.(A-9). The patient noted in applications 6, 7, and 8 above has now beendischarged from the hospital, and now presents to his physician's officefor follow-up. The same device can be used in physician's offices, as itprovides better care at lower cost.(A-10). Ambulances, emergency vehicles, and military vehicles can alsoemploy this device as it is very simple to operate, and provides datathat currently is impossible for them to obtain. In addition, theinformation can be transmitted to central stations where medicalpersonnel are available for help and advice.(A-11). The device and methods of the invention will provide means ofmonitoring patients or checking vital signs for extended carefacilities, nursing homes, and other health-related facilities.(A-12). Blood pressure screening clinics and drugstores will have agreatly improved means of determining patient's blood pressures andother vital signs. Airports and airplanes are able to purchase medicalequipment, but often do not have personnel trained to operate theequipment. The device is simple and quick to operate.(A-13). The patient noted in applications 6 through 9 above can alsomonitor his heart disease and health care at home. The operation of thedevice is straightforward enough to be used by the layman with minimalinstruction, and inexpensive enough for personal home use. The patientcan measure his cardiovascular characteristics daily, or as frequentlyas he and his physician desire. A communication means, such as a modem,can easily be incorporated into the device. This, with appropriatesoftware and support, would allow essentially instantaneouscommunication with a physician's office, clinic, or hospital. Inaddition, a permanent record can be made and stored electronically. Ifdesired, the device could automatically “sign on” to the Internet orother network, and link to the appropriate website or other address. Theability to participate more fully in their own health care will improvethe welfare of individuals.(A-14) The patient of above presents to the emergency room of a hospitalwith chest pain. The ER physician can access, via the Internet or othermeans, the patient's vital sign history, including ECG. This allows thephysician to determine if abnormalities are new or chronic. Changes,such as dysrhythmias, can be identified as to when they first occurred,perhaps to within a time frame of hours or less.(A-15). People without diagnosed cardiovascular disease can use thedevice to allow themselves to participate in their own health care. Thiswill allow virtually immediate diagnosis of any problems, allowing earlyintervention. In addition, a permanent record can be created if desired.(A-16). The device will impact fitness and physical training foreveryone from lay people to military personnel to professional athletes.(A-17). The device can be employed in the diagnosis and management ofperipheral vascular disease. Measurement of pulse wave velocity in theextremities, and particular differential pulse wave velocities in thelower extremities, can be used to diagnose peripheral vascular disease.Since measurements are real time and continuous, they can also be usedin management. For example, if balloon angioplasty of an artery isperformed, the clinician can tell immediately if flow has improved. Inthe case of angioplasty of coronary arteries, the clinician can followcardiac characteristics on a beat-by-beat basis.(A-18). In addition to peripheral vascular disease, other diseases, suchas abdominal aortic aneurysm, can be diagnosed and managed. Changes inpulse wave velocity and waveform can be followed for years if desired.(A-19). Some of the most important potential uses of the device relateto the health care of neonates and young children. For these patients,the measurement of common characteristics such as blood pressure can bedifficult even for highly trained personnel in well-equipped facilities.The simple placement of probes on fingers will alleviate this. Thedevice will also allow noninvasive diagnosis of congenital cardiacdefects and anomalies. Analysis of differential pulse wave velocity andblood pressure will allow rapid, accurate, and specific diagnosis ofmany disorders, including Tetralogy of Fallot and transposition of thegreat vessels. The ability to distinguish both arterial and venoussaturations and pressures will allow diagnosis of patent ductusarteriosus, truncus arteriosus, atrial septal defect, and ventricularseptal defect. Differential arm and leg pulse wave velocities andpressures will confirm diagnosis of coarctation of the aorta. Because ofits continuous measurements, the device can be used for only fordiagnosis but confirmation of adequacy of repair, includingintraoperatively. As the device is inexpensive and easy to operate, itmay become a screening tool for newborns and infants.(A-20). The device can be used in conjunction with intra-aortic balloonpump (IABP) counterpulsation. Beat-by-beat analysis of effectiveness andability to wean from counterpulsation can be made.(A-21). The device can be used in conjunction with placement of cardiacpacemakers, to set proper rate and timing intervals. In addition,efficacy of pacemakers can be checked as frequently as desired, andscheduling of reprogramming or replacement made automatically.(A-22). It is straightforward to incorporate other devices, such as theelectroencephalogram (EEG) or electromyogram (EMG), into probes of theinvention. As a general-purpose monitor, the device will invite theaddition of specialized add-ons.(A-23). Many enhancements are included in the invention. For example,addition of chest (horizontal) leads allows full diagnostic ECGs to beperformed.(A-24). Under some circumstances, such as severe hypotension, the pulsecannot be identified in the periphery. In such cases, many of thedeterminations claimed herein cannot be made. However, the ability ofthe device to identify venous blood can still give importantinformation.(A-25). Forces other than gravity can be used. In a microgravityenvironment such as a space station orbiting the Earth, a device such asthe one described could be constructed to perform all indicateddeterminations using acceleration caused by movement in place ofgravitational acceleration.(A-26). As mentioned in the examples above, an anticipated use is in thefield of home health care, with the possibility of automatic sign-on anddirection to a website. As the user is already participating in his orher health care, the extension of providing access to related health orother information via the Internet® is a natural one.(A-27). A verification means, such as fingerprint scanning, can beincorporated into a personal-use device, to ensure that any medicalinformation gathered belonged to the individual using the device.(A-28). The device will be used in conjunction with the Penaz techniqueor other methods, such as calibration with a cuff or other means, asdesired.(A-29). Nerve blocks, such as spinal or epidural anesthesia, block theactions of the sympathetic nervous system, producing both arterial andvenous dilation. This device can be used to assess these effects.(A-30). A patient with suspected peripheral vascular disease of thelower extremities is tested. A probe of the invention is placed on a toeof one foot, and an identical probe is placed on a toe of the otherfoot. Pulse velocities and possible pulse delay between the twoextremities are measured.(A-31). The patient from application 30 is tested further. Anotheridentical probe is placed on a finger. Pulse velocities and possiblepulse delay between the two lower extremities are measured. In addition,comparison is made with pulse velocity and propagation time in the upperextremity.(A-32). The patient from applications 30 and 31 is tested further. Thistime, the legs are raised and lowered to gain further information onpulse velocities and propagation times.(A-33). A person suffers severe trauma to the lower extremities in amotor vehicle accident. His physicians are concerned about thepossibility of his developing “compartment syndrome”, which iscompromise of blood supply due to swelling of injured tissues. Probes ofthe invention are placed on his feet to monitor the integrity of thevascular supply.(A-34). A pharmaceutical company develops a new drug to managehypertension, CHF, arrhythmias. Instead of long trials or invasivetrials, they are conducted on subjects using this device.(A-35). Taking vital signs on a space station. The techniques describedherein lend themselves well to the special problems of this uniqueenvironment.

BRIEF DESCRIPTION OF THE FIGURES

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawings, and in whichlike referenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIG. 1 is a diagram of the central cardiovascular system, showing theasymmetry of origins of the vessels off the aortic arch;

FIG. 2 is a partial perspective view of one embodiment of a physiologic“tissue” probe with a single emitter-detector pair, according to theinvention;

FIG. 3 is a partial perspective view of an alternative embodiment of atissue probe with a single emitter-detector pair, according to theinvention;

FIG. 4 is a partial perspective view of an alternative embodiment of atissue probe with two emitter-detectors, according to the invention;

FIG. 5 is a partial perspective view of an alternative embodiment of atissue probe with a single emitter-detector pair and a singleelectrocardiogram (ECG) electrode, according to the invention;

FIG. 6 is a partial perspective view of an alternative embodiment of atissue probe with a single emitter-detector pair and two ECG electrodes,according to the invention;

FIG. 7 is a partial perspective view of an alternative embodiment of atissue probe with a two emitter-detector pairs and two ECG electrodes,according to the invention;

FIG. 8 is a partial perspective view of an alternative embodiment of atissue probe having a position sensor, according to the invention;

FIG. 9 is a schematic illustration of a patient with tissue probesplaced on opposite digits according to the invention;

FIG. 10 is a schematic illustration of a patient with probes placed onopposite temples, according to the invention;

FIG. 11 is one embodiment of a circuit schematic including aphotoplethysmogram, according to the invention;

FIG. 12 is an alternative embodiment of a circuit schematic having aphotoplethysmogram with an ECG amplifier, according to the invention;

FIG. 13 is an alternative embodiment of a circuit schematic having aphotoplethysmogram with an ECG amplifier and a level signal, accordingto the invention;

FIG. 14 is an alternative circuit schematic having a photoplethysmogramwith two independent channels, according to the invention;

FIG. 15 is an alternative circuit schematic having a photoplethysmogramwith two independent channels and an ECG amplifier, according to theinvention;

FIG. 16 is a schematic illustration of a patient with tissue probesplaced on the digit and arm near the brachial artery, according to theinvention;

FIG. 17 is a schematic illustration of a patient with tissue probesplaced on a finger and toe, according to the invention;

FIG. 18 is a schematic illustration of a patient with tissue probesplaced on opposite fingers and a toe, according to the invention;

FIGS. 19 and 20 are schematic illustrations of patients with tissueprobes placed on opposite digits and positioned at differential heightsrelative to the patients' heart, according to the invention;

FIG. 21 is a schematic illustration of a patient with tissue probesplaced on a toe and opposite fingers positioned at different heights,according to the invention;

FIGS. 22-25 are graphical illustrations of oscilloscope tracings showingrecordings using methods of the invention wherein the probes are placedon index fingers of opposite hands, and the pulse velocities andrelative arrival times are varied by changing the heights of the probesrelative to the heart;

FIG. 26 is a graphical illustration of oscilloscope tracings showingtrains of pulses with varying oxygen saturation values;

FIG. 27 is a graphical illustration of oscilloscope tracings showingtrains of pulses with varying pH values;

FIG. 28 is a graphical illustration of oxygen saturation versus heartrate showing the effects of induced changes in oxygen saturationmeasured at the toe;

FIG. 29 is a graphical illustration of oxygen saturation versus heartrate showing the effects of induced changes in oxygen saturationmeasured at the left hand;

FIG. 30 is graphical illustration of oxygen saturation versus heart rateshowing the effects of induced changes in oxygen saturation measured atthe right hand;

FIGS. 31 and 32 are graphical illustrations of oxygen saturation (SO₂)versus pH showing the effect of plasma pH on oxygen saturationmeasurements for umbilical cord blood samples equilibrated with 100%oxygen;

FIG. 33 is a computer algorithm for determining hemoglobinconcentration, according to the invention;

FIG. 34 is a graphical illustration of optical extinction curves of fourspecies of hemoglobin at light wavelengths in the range of 600 to 950nm;

FIG. 35 is a graphical illustration of optical extinction curves forhemoglobin A at four different pH values and at light wavelengths in therange of 500 to 600 nm;

FIG. 36 is an absorption spectrum for oxyhemoglobin between measurementsat pH 7.6 and pH 6.8;

FIG. 37 is an absorption spectrum for carboxyhemoglobin betweenmeasurements at pH 7.6 and pH 6.8;

FIG. 38 is a graphical illustration of a normal hemoglobin-oxygendissociation curve (HODC);

FIG. 39 is a graphical illustration of HODC's showing shifts due to pHand temperature;

FIG. 40 is a graphical illustration of oxygen saturation versus heartrate showing the change of oxygen saturation corresponding to highcardiac fraction ejection; and

FIG. 41 is a graphical illustration of oxygen saturation versus heartrate showing a change of oxygen saturation corresponding to low cardiacfraction ejection.

DETAILED DESCRIPTION OF THE INVENTION

Functionally the heart is divided into two sides or sections. The rightor pulmonary circulation section that receives blood from the veins ofthe body and pumps it through the lungs and the left or systemiccirculation section that receives the blood from the lungs and pumps itto the body. The blood is then collected in the veins to be returned tothe right side of the heart.

Referring to FIG. 1, the arterial system begins at the aorta 1, to whichthe left ventricle of the heart pumps. The first three branches of theaorta are the brachiocephalic or innominate artery 2, the left (common)carotid artery 3, and the left subclavian artery 4. The brachiocephalicartery branches into the right subclavian 5 and right (common) 6 carotidarteries. These arteries provide the blood supply for the head and upperextremities. The aorta then passes down (caudal) through the body,continuing to provide arterial branches to organs, terminating as abifurcation creating the iliac arteries. The brachiocephalic orinnominate artery is the first branch of the aorta. It in turn branchesinto the right subclavian and right carotid arteries. In contrast, theleft subclavian and left carotid arteries originate directly off theaortic arch. Thus, the subclavian and carotid arteries and any of theirbranches to one side of the body have different paths from theircounterparts on the opposite side of the body.

Because of the different origins from the aorta and different branchingpattern of the arterial tree, it can be appreciated that blood ejectedfrom the left ventricle will not follow symmetrical pathways to oppositearms or body or opposite sides of the head. Similarly, the pressurepulse wave associated with left ventricular ejection will followdifferent pathways, and can be expected to arrive at different times forpaired organs or members of the upper body, or members of the upper bodycompared to the lower body.

Measurements performed by the inventor have shown this delay can rangefrom less than one millisecond to several milliseconds, depending on thesubject and circumstances. In addition, the inventor has found that thisdelay can be altered by several methods disclosed herein. Thispropagation delay, its alterations, and other factors make possibleseveral determinations heretofore not possible by noninvasive means.

Blood pressure is the pressure exerted by the blood within a vessel uponthe wall of the vessel. It is measured in units of force per unit area.Central venous pressure is the pressure within the large veins in thechest and the right atrium, which is the common emptying point for thevenous system. Cardiac output is the amount of blood pumped by theheart, expressed in units of volume per time.

Central venous pressure (CVP) is defined as the distending pressurepresent in the veins in the chest (proximate to the heart), and isconsidered equal to the pressure in the right atrium (which is theemptying point for the venous system). Pressure should be the samethroughout the venous system, but there are valves to ensure that theblood does flow back toward the heart (for example, when standing thevenous blood must flow uphill, and there is no pump as on the arterialside).

As discussed in detail below, the present invention generally includes aradiation emitter having at least one wavelength being applied through apatient's tissue to the patient's blood; a radiation detector whichdetects reception of the at least one wavelength after absorbancethrough the blood, a movement generator for inducing position changes inthe tissue; and a controller for computing the various characteristicsbased on the absorbance of the at least one wavelength of radiation atvarious position levels. In a preferred embodiment, the radiationemitter and detector are inserted in a probe which can be placed aboutthe tissue/blood to be measured. A number of suitable configurations forprobes are shown in FIGS. 2-8 and disclosed in Co-Pending applicationSer. No. 09/684,104, which is incorporated by reference herein.

For example, FIG. 2 shows a representative probe 10 with a singleemitter-detector pair 12. The emitter and detector are placed such thattransmittance through a body member, such as a finger 13, is measured.Generally, any part of the body that can be successfullytransilluminated with the radiant energy used can be utilized. Thus,toes, ears, etc. could also be used. In addition, pulse oximetry can beaccomplished with this and all of the following embodiments. FIG. 3shows a representative probe 14 with a single emitter-detector pair 16placed such that reflectance of a body member, such as a finger, ismeasured. Further, FIG. 4 shows a probe 18 with two emitter-detectorpairs 20 and 22 spaced a known distance apart. This can be used tomeasure the velocity of the pulse wave within the probe itself.

In certain embodiments of the invention, the probe comprises one or moreelectrocardiogram (ECG) electrodes in conjunction with theemitter-detector pairs. For example, FIG. 5 shows a probe 24 with asingle emitter-detector pair 26 and a single electrocardiogram (ECG)electrode 28. Similarly, FIG. 6 shows a probe 30 with a singleemitter-detector pair 32 and two ECG electrodes 34 and 36 and FIG. 7shows a probe 38 with two emitter-detector pairs 40 and 42 and two ECGelectrodes 44 and 46. Such probes, if placed on opposite extremities ofa patient, can be used to measure central and peripheral pulse wavevelocity as well as ECG. Other configurations, such as doubleemitter-detector pairs and single ECG electrode, can be envisioned.

In yet other embodiments of the invention, the probe further comprises aposition sensing or measuring device together with the emitter-detectorpairs and/or ECG electrodes. FIG. 8 shows a probe 48 similar to thatshown in FIG. 7 with the addition of a position sensor 50. This positionsensor could be used in conjunction with a position sensor placed atheart level in order to determine the hydrostatic pressure differencebetween the two position sensors.

As discussed in detail herein, the invention employs hydrostaticpressure to enable precise self-calibration of the devices in acompletely noninvasive manner. Hydrostatic pressure affects all liquids.Gravity or other acceleration will affect both the arterial and venoussides of the circulation. It affects all aspects of the blood pressureequally—mean, systolic, diastolic. For example, an increase in heightthat causes a change of 10 torr will change every pressure measurementduring the cardiac cycle by this amount.

For example, if the “true” blood pressure (taken level with the heart)is 120/80, when the arm is raised an amount needed to decrease themeasured pressure by 10 torr, the measured pressure in the arm will be110/70. The pulse pressure will be the same, but the transmural pressurewill be 10 torr lower at all times. In addition, the vessel will besmaller at all points.

The heart is taken to be the center of the circulatory system, and allvalues are in reference to it. This is not necessary for the practice ofthe invention, but serves as reference points for values in the currentmedical literature.

The electromagnetic radiation in this description will refer to light inthe visible and infrared range although, as noted in the attachedclaims, it is conceivable that other forms could be used.

Similarly, while the present invention primarily describes the use oftransillumination, it will be appreciated that reflectancespectrophotometry may alternatively be employed.

Operating Principles

It is well known that Incident radiation passing through a body part isattenuated (absorbed) in the tissue. The theoretical basis forspectrophotometric techniques is Beer's law (the Beer-Lambert-Bouguerlaw) which expresses the incident intensity in terms of transmittedintensity and extinction coefficients of the tissue compartments throughwhich the radiation has passed. The equation can be written as:

ln(I/Io)=E*C*L  Eq. 1

where:

Io=the incident intensity of the source radiation;

I=the transmitted intensity of the source through the sample;

E=the extinction coefficient of the component of interest;

C=the concentration of the component in the tissue itself;

L=the optical path length (distance) through the absorber; and

E*C*L=absorbance.

Beer's law and the practice of spectrophotometry and oximetry have beenexhaustively reviewed in the literature. Generally, pulse oximetry ineffect filters out signals other that pulsating (AC). In the body, itcan be assumed that the pulsatile component of the signal is arterialblood, while all other tissue absorbers should be non-pulsatile (DC).

An additional feature of this invention, not found in any previousdisclosure, is the use of hydrostatic pressure changes to vary not onlythe amount of arterial blood, but also the amount of venous blood withina body member such as a finger. Thus, hydrostatic changes can be used ina similar manner to the pulse to perform measurements on both arterialand venous blood. If a finger is contained within a probe, raising theprobe will lower the hydrostatic pressure of all vessels in the finger,both arterial and venous. Both arteries and veins (and arterioles andvenules) will be smaller due to lower pressure distending their walls.Most change will occur on the venous side of the circulation due tolower pressure. Total absorbance of the finger will decrease. As thearterial oxygen saturation can be measured by pulse oximetry, the venousoxygen saturation can be calculated in a similar manner.

A light signal of a known intensity and wavelength is produced by meansof light-emitting diodes (LEDs) as in currently used oximeters or, as inone possible embodiment, a broad-band light source whereby wavelengthsare isolated by a rotating filter or diffusion grating. In the lattercase, the emitted light is distilled through a filter which allows aknown wavelength and intensity of light to penetrate. Use of tunablelasers or other equipment is also possible. If the light source isproximate to the point of use, no further mode of transmission will beneeded. If it is not, the light will be transported to the desired pointby means such as a fiber optic cable, preserving the wavelength andintensity.

Several means of motion induction are possible. While a movementinduction means is described herein, voluntary movement or other meansare certainly possible. Various means of position measurement are alsopossible. For example, a liquid filled tube with an end open to theatmosphere can be employed. Other position sensors are known to thosehaving skill in the art, and include electromagnetic, spectroscopic,ultrasonic, and chemical means. Preferably, a broad-band photo detector(in the case of visible or infrared light) or other means is employed tomeasure the quantity of transmitted light.

To generate a single data point, the movement induction means is used tobring the finger (or other space of interest) to a known positionrelative to the heart. Light of known wavelength and intensity isemitted (and transmitted if necessary) on the surface of interest.Detection of the light signal at a distinct point (normally opposingsurface) is made and the relative absorbance and extinction of thesignal is calculated. Signal processing is used to determine thepulsatile portion of the signal. The arrival time of the pulse isrecorded, as is the amplitude and waveform. This measurement may berepeated one or more times to ensure the accuracy of the measurement;this can be done within a very short time frame (less than amillisecond).

To generate multiple data points, the process outlined in the previousstep will be repeated at the next chosen wavelength, while still at thesame predetermined position. The range and number of wavelengths can beselected, and changed for different applications.

Once the desired number of wavelengths has been examined, the movementinduction means would bring the finger or other volume to apredetermined second position, and the data collection of steps would berepeated. At the completion of measurements and determinations for thissecond position, the movement induction means will bring the space to athird predetermined position, and the measurements and determinationsrepeated. This process would be continued until the desired range ofpositions has been scrutinized.

In order to make computations of pulse propagation delay, identicalmeasurements would be made simultaneously with a probe on the samemember on the opposite side of the body. For example, if one probe wereplaced on the index finger of the right hand, the other probe would beplaced on the index finger of the left hand.

Because the arterial path to the arm is essentially identical after thesecond part of the subclavian artery, any differences in pulse wavevelocity and pulse wave propagation time must occur prior to this point;that is, very close to the root of the aorta. In any case, pulse wavevelocity increases rapidly as the pulse wave propagates down the aortaand into the periphery (Fung). Thus, any timing differences in theperiphery will be greatly reduced by the high wave velocity, leavingcentral effects as the most prominent.

The apparatus of the invention can be operated intermittently orcontinuously. In the intermittent mode, a single set of calculations canbe used for analysis to produce the determinations claimed. However, thedevice can also be easily operated in continuous mode, with the processoutlined above repeated as often as wished (constantly if desired). Inaddition, a rapid (“stat”) mode can be offered with the minimum numberof measurements made that will provide an accurate estimation of correctvalues. Such a rapid mode would be useful in emergency situations.

While this methodology should give precise values, further adjustmentmay be desired to compensate for any discrepancies between theoreticaland in vivo measurements. Contemporary oximeters in fact use acalibration curve when determining oxygen saturation, with the curvebeing generated with data from normal volunteers.

Calculations and Analysis

The following algorithms are further examples of the use of the presentinvention. Some variables have degrees of co-dependence. In these cases,values are calculated by iterative computational techniques.

According to the invention, measurement of pulse wave amplitude andtiming is made using probes such as that shown in FIG. 2, using methodssimilar to standard oximetry described in the prior art. Referring toFIG. 9, a first probe 52 is placed on a finger and set at a knownposition relative to the heart. Another, simultaneous measurement ofpulse wave amplitude and timing is made by a second probe 54 placed on afinger on the hand opposite that of the first probe. The pulse delayoccurring between the two measurements is made. Alternatively, as shownin FIG. 10, probes 52 and 54 can be placed on opposite temples of thepatient to measure pulse wave values and delay. The probes can also beplaced on the patient's ears.

From this information alone, an estimate of pulse wave velocity at theaortic root could be made, by utilizing a table of normal values for thedistance of the central anatomical difference.

If a measurement of blood pressure is then made, one can perform thefollowing calculation:

p=c*u*ρ  Eq. 2

where:

c=pulse wave velocity;

u=flow wave velocity; and

ρ=the density of the blood (approximately 1.055 grams/cm³).

According to the invention, p and c are measured, and ρ is known. Thisallows one to solve for u, which is the flow wave velocity at the aorticroot. This by itself is a measure of cardiac output. If one makes anestimate of aortic root diameter, one can then compute cardiac strokevolume.

According to the invention, various well-known, conventionalreconstruction techniques can be employed to convert or “transform”peripheral blood pressures and waveforms to the corresponding pressureand waveform at the aortic root. Ideally, the blood pressure at theaortic root should be used as the pressure term in Fung's equation.

One can improve on the above determination in several ways. The firstway is by additionally measuring the peripheral pulse wave velocity. Todo this, measurement of pulse wave amplitude and timing is made by afirst probe such as that shown in FIG. 5. The probe is at a set knownposition relative to the heart. Another, simultaneous measurement ofpulse wave amplitude and timing is made by a second probe placed on afinger on the hand opposite that of the first probe. The pulse delayoccurring between the two measurements is made. The respectiveperipheral pulse wave velocities are also computed. If the peripheralpulse wave velocities are different, it can be assumed that this isbecause of the different central anatomies from which the respectivepulses traveled. This information alone may be enough to compute centralpulse wave velocity from a table of normals. However, when combined withthe pulse wave delay information, this data enables one to construct afunction of pulse wave speed from the periphery back to the aortic root,thus giving another measure of central pulse wave velocity.

Another method of the invention is to vary the position of the probesrelative to the heart. If the first probe is at heart level and thesecond probe is raised above (with respect to the earth) heart level,the hydrostatic pressure of the blood vessels within the second probewill be lower than those within the first probe. In turn, in accordancewith Fung's equation stated above, this means that the pulse wavevelocity of the arterial vessels within the second probe will be lowerthan that in the arterial vessels within the first probe. This willchange both the measured pulse delay between the two probes, and themeasured peripheral pulse wave velocities. This creates additionalmeasurements by which to compute central pulse wave velocity.

According to the invention, changes in hydrostatic pressure arecontrolled by the following equation:

p=ρ*g*h  Eq. 3

where:

ρ=blood density;

g=gravitational acceleration (approximately 9.8 meters/sec²); and

h=height above a reference point (with respect to the earth).

The difference in hydrostatic pressure between the vessels in two probesis thus governed completely by their difference in heights relative tothe heart (referenced to the surface of the earth). Therefore, a knownchange in position produces a known change in hydrostatic pressure.

According to the invention, the above measurements can be employed toderive a number of physiological properties. Preferably, the probes ofthe invention are connected to a controller to aid the data collectionand analysis used to make the desired determination. The controllerincludes a computing device or standard personal computer (PC) with amonitor. Included within the controller are algorithms for thecalculation of variables not measured directly.

For example, referring to FIG. 11, there is shown a circuit schematicfor a one or two wavelength photo-plethysmograph. Emitters 56 and 58 anddetector 60 are positioned adjacent the tissue being measured, such as afinger 61. Emitters 56 and 58 are driven by drive circuitry 62, which isin turn governed by control signal circuitry 64. Detector 60 isconnected to amplifier 66. The signal from amplifier 66 is sent todemodulator 68, which is also synched to control signal circuitry 62.The signal from the demodulator 68 is sent to analog-digital converter70. The desired computations are performed on the output from theconverter 70 by signal processor 72 and the results sent to display 74.Emitters 56 and 58 operate specific wavelengths, such as 805 nm, and maycomprise light emitting diodes (LEDs) or laser diodes. Detector 60preferably comprises a silicon photodiode. Such emitter-detector pairsare shown in FIGS. 2 and 3.

Referring now to FIG. 12, there is shown a schematic of an alternateembodiment of suitable circuitry. As with FIG. 10, emitters 76 and 78are connected via LED drive circuitry 79 and control signal circuitry 80to demodulator 82. Signal from detector 84 is amplified at circuit block86 and sent to demodulator 82. Output from demodulator 82 is sent to A/Dconverter 88. In addition, ECG leads 90 are connected to differentialamplifier 92 and the signal is sent to converter 88. Output fromconverter 88 is processed at block 94 and the results sent to display96. A probe such as those shown in FIGS. 5 and 6 may be used with thecircuitry. The ECG leads are preferably silver/silver chloride orstainless steel.

Yet another embodiment of the invention is shown in FIG. 13. Emitters 98and 100 are connected via LED drive circuitry 101 and control signalcircuitry 102 to demodulator 104. Signal from detector 106 is amplifiedat circuit block 108 and sent to demodulator 104. Output fromdemodulator 104 is sent to A/D converter 109. ECG leads 110 areconnected to differential amplifier 112 and the signal is sent toconverter 109. Digit level sensor 114 and heart level sensor 116 areconnected to amplifier 118 and the signal is sent to converter 109.Output from converter 109 is processed at block 120 and the results sentto display 122.

Referring to FIG. 14, there is shown a circuit schematic suitable foruse with a probe having two physically independent channels, such as theone shown in FIG. 4. A first emitter-detector pair comprising emitters124 and 126 and detector 128 are positioned adjacent the tissue beingmeasured, such as a finger. A second pair comprising emitters 132 and134 and detector 136 are positioned a selected distance from the firstpair. Emitters 124, 126, 132 and 134 are driven by drive circuitry 138,which is in turn governed by control signal circuitry 140. Signal fromdetector 128 is amplified by block 142 and sent to demodulator 144.Independently, signal from detector 136 is amplified and demodulated atblocks 146 and 148, respectively. Output from demodulators 144 and 148is sent to analog-digital converter 150. The desired computations areperformed on the output from the converter 150 by signal processor 152and the results sent to display 154.

An alternative embodiment configured for use with a probe having twophysically independent channels and an ECG lead, such as the one shownin FIG. 7, is schematically illustrated in FIG. 15. A firstemitter-detector pair comprising emitters 156 and 158 and detector 160are positioned adjacent the tissue being measured, such as a finger. Asecond pair comprising emitters 164 and 166 and detector 168 arepositioned a selected distance from the first pair. Emitters 156, 158,164 and 166 are driven by drive circuitry 170 which is in turn governedby control signal circuitry 172. Signal from detector 160 is amplifiedby block 174 and sent to demodulator 176. Independently, signal fromdetector 168 is amplified and demodulated at blocks 178 and 180,respectively. Output from demodulators 176 and 180 is sent toanalog-digital converter 182. ECG leads 184 are connected todifferential amplifier 186 and the signal is also sent to converter 182The desired computations are performed on the output from the converter182 by signal processor 188 and the results sent to display 190.

As one of ordinary skill in the art will appreciate, the placement ofthe various probes discussed above will affect the types of measurementsthat can be taken. As discussed above, FIGS. 9 and 10 show probes placedon opposite extremities to enable measurement of pulse wave delay. FIG.16 shows an embodiment of the invention with probe 52, such as in FIG.1, placed on the digit, and a probe 54, such as in FIG. 2, placed on thearm near the brachial artery. This could measure the pulse wave velocityin the arm (as well as pulse oximetry). A similar embodiment couldmeasure pulse wave velocity in the leg. FIG. 17 shows probes 52 and 54placed on a finger and on a toe to measure the pulse wave delay.

FIG. 18 shows probes 52 and 54 placed on opposite digits and probe 55placed on a toe. This allows measurement of the differential pulse wavedelay between the fingers and toe, and allows calibration of the toeprobe to be used in place of a finger probe (if only one finger probecould be used, such as in hand surgery). The use of appropriate probesalso allows a diagnostic-quality ECG.

FIGS. 19 and 20 show probes 52 and 54 placed on opposite digits. One armof the subject is placed at the level of the heart, while one arm ismoved to different positions, both above and below the level of theheart. By generating different hydrostatic pressures in the vessels, thepulse velocity and hence pulse wave delay changes. In addition, theamplitude of the pulse wave, and amplitude of venous absorbance changes.This allows the additional computations of arterial blood pressure andvenous pressure.

FIG. 21 shows probes 52 and 54 placed on opposite digits and probe 55placed on a toe. The differential hydrostatic pressures in the vesselsallow measurements of pulse wave velocity and pulse wave delay, as wellas arterial blood pressure and venous pressure. Use of probes withsuitable ECG leads will also allow the invention to perform adiagnostic-quality ECG. In addition, heart rate and respiratory rate canbe calculated, and cardiac output and several other cardiovascularcharacteristics computed.

As discussed above, the controllers of the invention preferably outputthe results of the measurements and computations to a display. Referringnow to FIG. 22, there are shown two oscilloscope tracings from pulseoximeter probes, such as those shown in FIG. 1, placed on the indexfingers of both hands. The pulse wave delay is visible as the slightphase difference between the two tracings. As the probes are at the samelevel, the pulse amplitudes are essentially identical.

Referring to FIG. 23, there are shown oscilloscope tracings for a probeon a hand placed at a level higher than the heart (Curve A) and a probeon a hand placed at a level lower than the heart (Curve B). Theinduction of a pressure differential between the two probes effects achange in the pulse delay. The change in pressure also correspondinglyalters the pulse amplitudes.

Referring now to FIG. 24, there are shown oscilloscope tracings for aprobe on a hand placed at a level lower than the heart (Curve A) and aprobe on a hand placed at a level higher than the heart (Curve B). Here,the pulse delay has substantially reversed as have the pulse amplitudes.FIG. 25 are oscilloscope tracings showing an electrocardiogram (Curve A)in conjunction with a pulse waveform (Curve B).

The algorithms outlined below serve as examples, but modifications arepossible to arrive at the indicated results, and are meant to beincluded within the spirit of this application. Various additionalcomponents of the device will be discussed in more detail below withreference to the following exemplary determinations.

(D-1). Determination of Arterial Blood Pressure

A probe, such as that shown in FIG. 1, is placed on an extremity that ismoved in relation to the heart. As mentioned above, the hydrostaticpressure within the arteries and arterioles changes as a function ofheight with respect to the heart. Because of this, both the pulse wavevelocity and pulse wave amplitude change as a function of probe height.These two parameters can be mapped against known distance above or belowthe heart. In this way, function curves of pressure vs. pulse waveamplitude and pressure vs. pulse wave velocity can be drawn. Forexample, a full excursion of the arm in a standing adult produceshydrostatic changes of greater than 50 cm of water in both directions.Using an arm and a leg, a gradient of well over 200 cm of water can begenerated. This is a significant portion of the normal blood pressurerange, and certainly enough to produce the function curves mentionedabove.

There is a huge amount of medical literature describing arterialbehavior, so the curves can be extrapolated if necessary. These curvesserve as calibration.

It can thus be determined if “recalibration” is necessary—if eitherpulse amplitude or pulse wave velocity changes, and the other parameterdoes not change correspondingly. In other words, a shift on one curveshould be matched by a corresponding shift on the other curve. If thisshift does not occur as predicted, recalibration is required. Of course,the process of recalibration is the simple procedure outlined above.

In a preferred embodiment, a first probe having a position sensor isplaced level with the patient's heart. A second probe, such as one shownin FIG. 8, having a position sensor and a pulse detector is placed onthe patient's finger. The patient's arm is held out level with the heartso there is zero displacement between probes. Pulse amplitude isrecorded from probe. The patient's arm is slowly raised, while pulseamplitude and relative displacement of probe are recorded. Thehydrostatic pressure difference between probes is also computed.

By comparing the recorded pulse amplitude to the hydrostatic pressuredifference, a mathematical function relating pressure to pulse amplitudecan be derived. Preferably, circuitry similar to that shown in FIG. 13is used to aid the process. This process is repeated while lowering thearm back to heart level, then lowering the arm to below heart level and,finally, raising the arm back to heart level. Similar steps can beapplied to measure pulse delay, pulse velocity and pulse contour. Alsopreferably, frequency or Fourier analysis may be used to make therequisite determinations.

(D-2). Determination of Cardiac Output

Cardiac output can be determined by measuring delays in pulse arrivaltimes in coupled organs or members on opposite sides of the body. In apreferred embodiment of the invention, probes such as those shown inFIG. 1, having sensors for detecting a patient's pulse are placed onopposite fingers of the patient. The patient positions both armsstraight out from the side. The blood pressure of the patient can bedetermined either through conventional means or by the methods of theinvention. The pulse delay between the two probes can be measuredutilizing circuitry such as that shown in FIG. 14 or 15, for example.The dicrotic notch of the pulse may be determined by standard methods,and used to calculate the ejection time based on the timing. The size ofthe aortic root can be estimated by standard means and the consequentlythe pulse distance differential at the aortic root. This allows thecalculation of the pulse velocity c at the aortic route by the followingequation:

c=(pulse distance)/(pulse delay)  Eq. 4

The value of c can then be used to determine the flow wave velocitybased on the following equation:

p=c*u*ρ  Eq. 5

where:

c=pulse wave velocity;

u=flow wave velocity; and

ρ=density of the blood (approximately 1.055 grams/cm³).

According to the invention, cardiac stroke volume can be determined bymultiplying the aortic root area by the flow wave velocity and by thecardiac ejection time. Cardiac minute output can be calculated bymultiplying the cardiac stroke volume by the pulse rate. These steps canbe augmented by raising and lowering the patient's arms with respect toeach other to vary the pressure and the pulse wave velocity.

Experiments by the inventor using a “single breath of oxygen” techniqueoutlined below have shown that having the arms at different levels (andthus, different arterial blood pressures) results in different bloodflows to the arms. The blood flow is thus obeying the classic fluidicversion of Ohm's law:

p=f*r  Eq. 6

where:

p=pressure

f=flow

r=resistance

Because of this, varying the pressure by small amounts (large amountswould cause changes in autoregulation) can be used to calculate bloodflow and thus cardiac output. Since the pulse arrives at the two handsat different times, if the “faster” arm is raised, the pulse wavevelocity slows. The pressure difference necessary to make the pulsearrive in both hands simultaneously can be calculated. In view of thepressure-flow relationship above, the ratio of pressure should be thesame as the ratio of flow. The time difference, or number of heartbeats,of the flow arrivals in the two hands when they are level with the heartcan be computed. In turn, this gives the cardiac index, as the closerthe flow arrival times are, the higher the cardiac output. Likewise, thegreater the flow arrival time difference is, the lower the cardiacoutput.

Alternatively, cardiac output can be determined by placing probes suchas those shown in FIG. 5 on a patient's finger and toe. The probesmeasure oxygen saturation at each pulse. The oxygen saturation for eachpulse at the first probe is compared to the oxygen saturation of thatpulse and subsequent pulses at the second probe. With continuousmonitoring, this allows the determination matching oxygen saturation,within given tolerance limits, of the pulses from the probes. Thepatient's blood volume and the physical separation of the probes can bedetermined by standard methods. This allows the computation of cardiacstroke volume by dividing the blood volume displaced by the number ofpulses. Then, the cardiac minute output can be calculated by multiplyingthe cardiac stroke volume by pulse rate. Circuitry such as that shown inFIG. 11 or 12 is suitable for use with this embodiment.

In yet another embodiment, the principles used above may be used tocalculate cardiac output on the basis of flow wave propagation asopposed to pulse wave. As described above, the propagation of the flowwave (physical passage of blood through the arterial system) happensmuch more slowly than that of the pulse wave (celerity). Thus, bloodthat is ejected during a single cardiac cycle will arrive at the twohands at a slightly different time, while the time difference betweenthe arrival at a hand versus a foot may be much longer, in the order ofseveral seconds.

The difficulty lies in determining the blood that was ejected during thesame cardiac cycle. Two parameters that can be used to determine thisare the hemoglobin oxygen saturation and the pH (acid-base balance). Aswill be discussed below in their respective sections, hemoglobinconcentration and blood pH can be measured using the probes andtechniques of the invention. All blood that is ejected during a singlecardiac cycle can be assumed to have the same saturation and pH, becauseblood is very well mixed in the left atrium and left ventricle prior toejection. Also, it can be assumed that the saturation and pH change verylittle during the passage of the blood through the arterial system, asthe arteries behave like pipes, conveying the liquid but consuming orreleasing minimal metabolites.

Both the saturation and pH change slightly in a continuous fashion dueto the respiratory cycle and other factors. In addition, large changescan be caused by maneuvers such as voluntary hyperventilation orbreathholding. Because of this, a pattern in either the saturation orthe pH can be recognized, allowing one to “match” the pulses whichreflect the blood ejected during the same heartbeat. The difference inarrival times can then be used to compute the cardiac output. By way ofillustration, referring to FIG. 26, the first pulse train (Curve A)corresponds to the hand. The second pulse train (Curve B), which arriveslater, corresponds to the foot.

FIG. 27 similarly illustrates this phenomenon for pulses of differingpH. The first pulse train (Curve A), which arrives earlier, correspondsto the hand. The second pulse train (Curve B) corresponds to the foot.According to the invention, additional, known parameters in addition tooxygen saturation and pH can also be employed.

As is well known in the art, oxygen saturation varies a small amountnormally, even in the “steady state”. The idea is that this variationcan be used to “match” pulses that are of the same saturation, but are“out of phase.” That is, they arrive at different parts of the body(opposite hands or hand and foot, for example) at different times.Changes in pH follow similar patterns. Referring to FIGS. 28-30, thereare shown induced changes in oxygen saturation caused by a single breathof oxygen, as measured by probes on the toe (FIG. 28), left hand (FIG.29) and right hand (FIG. 30), respectively.

The concept of induced change in either oxygen saturation of pH is veryimportant. Taking one of more breaths of oxygen will raise one's oxygensaturation. If one is already receiving oxygen therapy, then taking oneof more breaths of a higher inspired concentration of oxygen (“richermixture”) will do. Conversely, breath holding, or breathing a gas otherthat oxygen, such as nitrogen, will decrease your oxygen saturation. ForpH, breath holding or breathing a gas mixture containing carbon dioxidewill lower your blood pH, whereas rapid breathing will raise your pH. Asshown in FIGS. 28-30, the rise starts a few heartbeats earlier on theright hand compared to the left, and the foot is many beats later.

For computing a value for cardiac output, the method is that an indexcan be generated based on patient's height or body surface area (BSA).The delay in the arrival of a given pulse (identified by saturation orpH) between different parts of the body generates an index for each pairof points. For example, the longer the delay between hand and foot, thelower the cardiac output. The shorter the delay, the higher the cardiacoutput.

With the addition of the induced saturation change (or pH), one cancalculate all these indices more easily (since the change is morenoticeable and easier to measure). Importantly, however, there isanother index—the time between the breath inspiring the increased oxygenand the first heart beat in which the change is noted. This is the sameprinciple—the shorter this time period, the greater the cardiac output,and the longer the time, the lower the flow.

In summary, giving a subject a single breath of oxygen and continuouslymeasuring the oxygen saturation in an extremity can be used for 3measurements. First, the time or number of heartbeats from theinspiration to the first change of saturation in the extremity (firstpulse that has different saturation from baseline) can be used tocompute the cardiac index (and thus cardiac output and stroke volume).Second, the time or number of heartbeats from the beginning of thechange in saturation to the maximum change can be used to compute thecardiac ejection fraction. Finally, the time intervals of total timefrom inspiration until the saturation has returned to baseline, totaltime from beginning of saturation change to return to baseline and“rebound” in saturation after return to baseline can be used to computeblood volume.

(D-3). Determination of Venous Saturation and Pressure

Determination of arterial oxygen saturation can be determined by pulseoximetry and techniques well delineated in both the patent and medicalliterature. Hydrostatic changes as described in this application allowthe determination of venous saturation and pressure as well.

Place a probe, such as that shown in FIG. 1, on a finger. Makemeasurements of both total absorbance and pulsatile absorbance. Raisethe probe a known distance. Again measure both total absorbance andpulsatile absorbance. Both will be decreased. This is because the pulseamplitude is less because the arterial blood pressure within the probeis less (due to decrease in hydrostatic pressure). However, the totalabsorbance will also decrease, as the distending pressure in the venoussystem is less, and hence the veins and venules are smaller. All changesin absorbance can be assumed to be due to changes in blood volume.Saturation is calculated using the ratios of absorbance of distinctwavelengths.

In one embodiment, the central venous pressure (CVP) can be estimated. Aprobe containing a position sensor is place level with a patient'sheart. A second probe, such as the one shown in FIG. 8, also comprisinga position sensor is placed on the patient's finger. The patientpositions the arm so that the second probe is initially lower than thefirst probe. The total absorbance measured at the second probe iscontinuously monitored. The patient's arm is slowly raised, and the rateof change of absorbance of the second probe is computed with respect tothe relative displacement to the first probe. When the rate of changechanges by a predetermined amount representing an abrupt decrease, thearm position corresponding to the point of central venous drainage hasbeen reached. The CVP can then be calculated by computing thehydrostatic pressure difference between the first probe and the secondprobe at that arm position. The circuitry shown in FIG. 13 is suitablefor use with this embodiment.

(D-4). Determination of Hemoglobin Concentration

Pulse oximeters in clinical use measure hemoglobin absorbance at 2different wavelengths, commonly 660 and 940 nanometers (nm). Ratiometricanalysis of the 2 absorbances at the 2 wavelengths allow determinationof the relative amounts of the 2 species of hemoglobin, oxyhemoglobinand deoxyhemoglobin, which normally constitute blood. Standard 2wavelength oximeters assume that there only these 2 species. Thoughothers may be present, they are usually so in very low concentrations.

As discussed above, the basic equation governing the absorbance of lightis Beer's Law:

A=E*C*L  Eq. 7

where:

A=absorbance;

E=the extinction coefficient;

L=the path length of light travel; and

C=concentration of hemoglobin.

The extinction coefficient of the medium through which the light isbeing transmitted can be thought of as transparency or opacity.

Using this nomenclature, the absorbance of the 660 nm wavelength isA₆₆₀, and the absorbance of the 940 nm wavelength is A₉₄₀. Also, oxywill refer to oxyhemoglobin and deox to deoxyhemoglobin.

Writing out the absorbances in terms of Beer's Law provides:

A ₆₆₀ =E _(660oxy) *C _(oxy) *L+E _(660deox) *C _(deox) *L  Eq. 8

A ₉₄₀ =E _(940oxy) *C _(oxy) *L+E _(940deox) *C _(deox) *L  Eq. 9

As sampling can be performed very quickly (optically andelectronically), it can be assumed that path length L does not changebetween 2 successive measurements. Thus, L will cancel out when adivision is performed.

$\begin{matrix}{\frac{A_{660}}{A_{940}} = \frac{{E_{660{oxy}}*C_{oxy}*L} + {E_{660{deox}}*C_{deox}*L}}{{E_{940{oxy}}*C_{oxy}*L} + {E_{940{deox}}*C_{deox}*L}}} \\{= \frac{{E_{660{oxy}}*C_{oxy}} + {E_{660{deox}}*C_{deox}}}{{E_{940{oxy}}*C_{oxy}} + {E_{940{deox}}*C_{deox}}}}\end{matrix}$

This can then be combined:

E _(660oxy) *C _(oxy) *A ₉₄₀ +E _(660deox) *C _(deox) *A ₉₄₀ =E_(940oxy) *C _(oxy) *A ₆₆₀ +E _(940deox) *C _(deox) *A ₆₆₀

With rearrangement:

E _(660oxy) *C _(oxy) *A ₉₄₀ −E _(940oxy) *C _(oxy) *A ₆₆₀ =E _(940deox)*C _(deox) *A ₆₆₀ −E _(660deox) *C _(deox) *A ₉₄₀

C _(oxy)*(E _(660oxy) *A ₉₄₀ −E _(940oxy) *A ₆₆₀)=C _(deox)*(E_(940deox) *A ₆₆₀ −E _(660deox) *A ₉₄₀)

C _(oxy) /C _(deox)=(E _(940deox) *A ₆₆₀ −E _(660deox) *A ₉₄₀)/(E_(660oxy) *A ₉₄₀ −E _(940oxy) *A ₆₆₀)

As the absorbances are measured and the extinction coefficients areknown experimentally, this allows computation of C_(oxy)/C_(deox).Designating this ratio R_(s), the oxygen saturation of the blood (S) canbe computed and the percentage of the blood that is oxyhemoglobin fromthe following:

S=R _(s)/(1+R _(s))  Eq. 10

Unfortunately, Eq. 10 only allows determination of the ratio of the 2species of hemoglobin, not the total concentration of hemoglobin, morecommonly termed the “blood count”.

The inability of previous attempts to determine hemoglobin concentrationfrom absorbance measurements is because Beer's Law has 2 unknowns, C andL, with only a single measurement, A. As C and L are products, it isimpossible to distinguish between them. Forming another equation bymaking another measurement of absorbance at, for example, a differentpath length, the new absorbance is simply a multiple of the first, andno new information is gained.

It will thus be appreciated that what is needed is the substitution foreither C or L in a way that they are no longer linearly coupled. Since anon-linear result is desirable, multiplication or logarithms would begood choices to manipulate the equation.

An absorbance measurement for hemoglobin can be expressed as:

A=C*L*k  Eq. 11

where:

-   -   k=a value based on the extinction coefficients for the        wavelength and the oxygen saturation of the blood.

If there is only one species of hemoglobin present, k is the extinctioncoefficient for that wavelength. Dividing out this known value toprovides:

A ₁ =C*L ₁  Eq. 12

The absorbance measurements can then be taken at a different pathlength, resulting in different values for A₁ as well as L₁. However, itis not necessary to repeat measurements, as once absorbance values for agiven path length are known, so are the values for all possible pathlengths. This also holds for saturation.

A ₂ =C*L ₂  Eq. 13

Multiplying these Equations 11 and 12 provides:

A ₁ *A ₂ =C*L ₁ *C*L ₂ =C ² *L ₁ *L ₂

Further, taking the logarithm of the new equation provides:

log(A ₁ *A ₂)=2 log(C)+log(L ₁)+log(L ₂)  Eq. 14

Since the arithmetic operations may be performed in reverse order, thiscan be rewritten as:

log(L ₁)+log(L ₂)=log(A ₁ *A ₂)−2 log(C)  Eq. 15

Taking logarithms first:

log(A ₁)=log(C)+log(L ₁)  Eq. 16

log(A ₂)=log(C)+log(L ₂)  Eq. 17

Next, multiplying these terms provides:

log(A ₁)*log(A ₂)=[log(C)+log(L ₁)]*[log(C)+log(L ₂)]  Eq. 18

=log²(C)*log(C)*[log(L ₁)+log(L ₂)]+log(L ₁)*log(L ₂)  Eq. 19

Substituting the term [log(L₁)+log(L₂)] in Equation H2 provides:

$\begin{matrix}{{{\log \left( A_{1} \right)}*{\log \left( A_{2} \right)}} = {{\log^{2}(C)} + {{\log (C)}*\left\lbrack {{\log \left( {A_{1}*A_{2}} \right)} - {2{\log (C)}}} \right\rbrack} + {{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}}}} & {{Eq}.\mspace{14mu} 20}\end{matrix}$

Rearrangement provides:

$\begin{matrix}\begin{matrix}{{{\log \left( A_{1} \right)}*{\log \left( A_{2} \right)}} = {{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} + {{\log (C)}*}}} \\{{{\log \left( {A_{1}*A_{2}} \right)} - {{\log (C)}*2{\log (C)}} +}} \\{{\log^{2}(L)}} \\{= {{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} + {{\log (C)}*}}} \\{{{\log \left( {A_{1}*A_{2}} \right)} - {2{\log^{2}(C)}} + {\log^{2}(C)}}} \\{= {{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} + {{\log (C)}*}}} \\{{{\log \left( {A_{1}*A_{2}} \right)} - {\log^{2}(C)}}}\end{matrix} & {{Eq}.\mspace{14mu} 21}\end{matrix}$

As above, taking the absorbance measurements at different path lengths,will give different values for A₁ and A₂, as well as L₁ and L₂. Thesenew values are all multiples of our original A₁ and L₁. Subscripts 3 and4 are used to denote these new equations (measurements). The equationsthus become:

log(A ₁)*log(A ₂)=log(L ₁)*log(L ₂)+log(C)*log(A ₁ *A ₂)−log²(C)  Eq. 22

log(A ₃)*log(A ₄)=log(L ₃)*log(L ₄)+log(C)*log(A ₃ *A ₄)−log²(C)  Eq. 23

Since the term log²(C) occurs in both equations, the term will beeliminated if the equations are subtracted from each other. Thussubtracting Equation 23 from Equation 22 provides:

$\begin{matrix}{{{{\log \left( A_{1} \right)}*{\log \left( A_{2} \right)}} - {{\log \left( A_{3} \right)}*{\log \left( A_{4} \right)}}} = {{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} + {{\log (C)}*{\log \left( {A_{1}*A_{2}} \right)}} - {\log^{2}(C)} - {\quad{\left\lbrack {{{\log \left( L_{3} \right)}*{\log \left( L_{4} \right)}} + {{\log (C)}*{\log \left( {A_{3}*A_{4}} \right)}} - {\log^{2}(C)}} \right\rbrack = {{{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} - {{\log \left( L_{3} \right)}*{\log \left( L_{4} \right)}} + {{\log (C)}*{\log \left( {A_{1}*A_{2}} \right)}} - {{\log (C)}*{\log \left( {A_{3}*A_{4}} \right)}}} = {{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} - {{\log \left( L_{3\;} \right)}*{\log \left( L_{4} \right)}} + {{\log (C)}*\left\lbrack {{\log \left( {A_{1}*A_{2}} \right)} - {\log \left( {A_{3}*A_{4}} \right)}} \right\rbrack}}}}}}} & {{Eq}.\mspace{14mu} 24}\end{matrix}$

These manipulations have broken the linear coupling of C and L, as Loccurs as a square in this expression, while C has an exponent of 1.Further, the A terms are in different combinations on opposite sides ofthe equation. In addition, multiplying either C or L by a given factorresults in a different equation, not just a multiple of the sameequation. New equations can thus be formed by taking multiples of eitherL or C.

This equation also answers the questions: How can you tell C and Lapart? How do you know that C is not half as large and L twice as large?The absorbance measurement is still the same.

If L1 is doubled and C halved, the A values should not change. Thus theleft hand side of Equation 24 will not change. For the right hand side,halving C causes the value of the C term to decrease by:

log 2*[log(A₁*A₂)−log(A₃*A₄)]  Eq. 25

Since the value of all the L will increase by log 2, the quantity of theL term will be:

$\begin{matrix}{{{{\log \left( {L_{1}*2} \right)}*{\log \left( {L_{2}*2} \right)}} - {{\log \left( {L_{3}*2} \right)}*{\log \left( {L_{4}*2} \right)}}} = {{{\left\lbrack {{\log \left( L_{1} \right)} + {\log \; 2}} \right\rbrack*\left\lbrack {{\log \left( L_{2} \right)} + {\log \; 2}} \right\rbrack} - {\left\lbrack {{\log \left( L_{3} \right)} + {\log \; 2}} \right)*\left\lbrack {{\log \left( L_{4} \right)} + {\log \; 2}} \right\rbrack}} = {{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} + {\log \; 2*\left( {{\log \; L_{1}} + {\log \; L_{2}}} \right)} + {\log^{2}2} - {\quad{\left\lbrack {{{\log \left( L_{3} \right)}*{\log \left( L_{4} \right)}} + {\log \; 2*\left( {{\log \; L_{3}} + {\log \; L_{4}}} \right)} + {\log^{2}2}} \right\rbrack = {{{\log \left( L_{1} \right)}*{\log \left( L_{2} \right)}} - {{\log \left( L_{3} \right)}*{\log \left( L_{4} \right)}} + {\log \; 2*\left( {{\log \; L} + {\log \; L_{2}} - {\log \; L_{3}} - {\log \; L_{4}}} \right)}}}}}}} & {{Eq}.\mspace{14mu} 26}\end{matrix}$

Subtracting the original L term causes a change of:

log 2*(log L₁+log L₂−log L₃−log L₄)  Eq. 27

This is not equal to the change in the C term (if it were, L could besolved in terms of A), so C and L are not interchangeable.

Referring to Equation 24, it is noted that the log(C) term could beeliminated if new equations with 4 different path lengths were formedand the process repeated. There is nothing preventing this, as anynumber of equations at different path lengths can be formed, and allwill be different.

log(A ₅)*log(A ₆)−log(A ₇)*log(A ₈)=log(L ₅)*log(L ₆)−log(L ₇)*log(L₈)+log(C)*[log(A ₅ *A ₆)−log(A ₇ *A ₈)]  Eq. 28

To subtract Equation 28 from Equation 24, the coefficients of the log(C)terms must be equal, so Equation 28 is multiplied by the following term:

[log(A₁*A₂)−log(A₃*A₄)]/[log(A₅*A₆)−log(A₇*A₈)]

To simplify, constants values that are known or already measured ordetermined are represented.

k ₁₂₃₄=log(A ₁)*log(A ₂)−log(A ₃)*log(A ₄)  Eq. 29

k ₅₆₇₈=log(A ₅)*log(A ₆)−log(A ₇)*log(A ₈)  Eq. 30

k _(d)=[log(A ₁ *A ₂)−log(A ₃ *A ₄)]/[log(A ₅ *A ₆)−log(A ₇ *A ₈)]  Eq.31

A new equation is formed by multiplying Equation 28 by k_(d). Thisensures that the log(C) terms are equal. Subtracting this new equationfrom Equation 24 eliminates the log(C) term:

k ₁₂₃₄−(k _(d) *k ₅₆₇₈)=log(L ₁)*log(L ₂)−log(L ₃)*log(L ₄)−k _(d)[log(L₅)*log(L ₆)−log(L ₇)*log(L ₈)]

At this point, an equation with a constant (known number value) on oneside, and 4 terms in log(L) on the other is obtained. Equations at 8path lengths have been used, but these path lengths are all knownmultiples of each other. Thus, the equations can be expressed as:

L ₂ =L ₁ *A ₂ /A ₁  Eq. 32

L ₃ =L ₁ *A ₃ /A ₁  Eq. 33

L ₄ =L ₁ *A ₄ /A ₁  Eq. 34

L ₅ =L ₁ *A ₅ /A ₁  Eq. 35

L ₆ =L ₁ *A ₆ /A ₁  Eq. 36

L ₇ =L ₁ *A ₇ /A ₁  Eq. 37

L ₈ =L ₁ *A ₈ /A ₁  Eq. 38

The equation now becomes:

$\begin{matrix}\begin{matrix}{{k_{1234} - \left( {k_{d}*k_{5678}} \right)} = {{{\log \left( L_{1} \right)}*{\log \left( {L_{1}*{A_{2}/A_{1}}} \right)}} -}} \\{{{{\log \left( {L_{1}*{A_{3}/A_{1}}} \right)}*{\log \left( {L_{1}*{A_{4}/A_{1}}} \right)}} -}} \\{{k_{d}*{\log \left( {L_{1}*{A_{5}/A_{1}}} \right)}*}} \\{{{\log \left( {L_{1}*{A_{6}/A_{1}}} \right)} + {k_{d}*}}} \\{{{\log \left( {L_{1}*{A_{7}/A_{1}}} \right)}*{\log \left( {L_{1}*{A_{8}/A_{1}}} \right)}}} \\{= {{{\log \left( L_{1} \right)}*\left\lbrack {{\log \left( L_{1} \right)} + {\log \left( {A_{2}/A_{1}} \right)}} \right\rbrack} -}} \\{{\left\lbrack {{\log \left( L_{1} \right)} + {\log \left( {A_{3}/A_{1}} \right)}} \right\rbrack*}} \\{{\left\lbrack {{\log \left( L_{1} \right)} + {\log \left( {A_{4}/A_{1}} \right)}} \right\rbrack - {k_{d}*}}} \\{{\left\lbrack {{\log \left( L_{1} \right)} + {\log \left( {A_{5}/A_{1}} \right)}} \right\rbrack*}} \\{{\left\lbrack {{\log \left( L_{1} \right)} + {\log \left( {A_{6}/A_{1}} \right)}} \right\rbrack + {k_{d}*}}} \\{{\left\lbrack {{\log \left( L_{1} \right)} + {\log \left( {A_{7}/A_{1}} \right)}} \right\rbrack*}} \\{\left\lbrack {\log\left( {L_{1} + {\log \left( {A_{8}/A_{1}} \right)}} \right\rbrack} \right.} \\{\left. {= {{\log^{2}\left( L_{1} \right)} + {{\log \left( L_{1} \right)}*{\log \left( {A_{2}/A_{1}} \right)}}}} \right\rbrack -} \\{{\begin{bmatrix}{{\log^{2}\left( L_{1} \right)} + \begin{bmatrix}{\log \left( L_{1} \right)*} \\\left( {{\log \left( {A_{3}/A_{1}} \right)} +} \right. \\{\log \left( {A_{4}/A_{1}} \right)}\end{bmatrix} +} \\{{\log \left( {A_{3}/A_{1}} \right)}*{\log \left( {A_{4}/A_{1}} \right)}}\end{bmatrix} -}} \\{{{k_{d}*\begin{bmatrix}{{\log^{2}\left( L_{1} \right)} + {{\log \left( L_{1} \right)}*}} \\{{\log \left( {A_{5}/A_{1}} \right)} + {\log \left( {A_{6}/A_{1}} \right)}}\end{bmatrix}} +}} \\{\left. {{\log \left( {A_{5}/A_{1}} \right)}*\left( {A_{6}/A_{1}} \right)} \right\rbrack + {k_{d}*}} \\{\begin{bmatrix}{{\log^{2}\left( L_{1} \right)} + \begin{bmatrix}{\log \left( L_{1} \right)*} \\\left( {{\log \left( {A_{7}/A_{1}} \right)} +} \right. \\{\log \left( {A_{8}/A_{1}} \right)}\end{bmatrix} +} \\{{\log \left( {A_{7}/A_{1}} \right)}*{\log \left( {A_{8}/A_{1}} \right)}}\end{bmatrix}}\end{matrix} & {{Eq}.\mspace{14mu} 39}\end{matrix}$

As noted, the log² terms have coefficient 1. Further, since 2 terms areadded while 2 are subtracted they will be eliminated.

Combining all the A terms (which are known) that occur as coefficients,creates k_(Ac). Then, combining all the A terms that occur alone(k_(Aa)), the equation becomes:

k ₁₂₃₄−(k _(d) *k ₅₆₇₈)=log(L ₁)*k _(Ac) +k _(Aa)  Eq. 40

where:

log(L ₁)=[k ₁₂₃₄−(k _(d) *k ₅₆₇₈)−k _(Aa) ]/k _(Ac)

L ₁=antilog{[k ₁₂₃₄−(k _(d) *k ₅₆₇₈)−k _(Aa) ]/k _(Ac)}

This leaves a single unknown, L₁. Note that all A values are different,so neither side of the equation should be zero. If this does occur,choice of one or more different A values will guarantee a non-zeroresult.

Since the equation has been solved for L₁, returning to the originalequation provides:

A ₁ =C*L ₁  Eq. 41

C=A ₁ /L ₁  Eq. 42

Now, the concentration of hemoglobin, C, can be solved. An example of asuitable computational algorithm is provided in FIG. 33.

A similar analysis can be performed, varying C instead of L. Maintainingthe assumption of only 2 species of hemoglobin, then the wavelengthabsorbances can be expressed as:

$\begin{matrix}{A_{660} = {A_{660{oxy}} + A_{660{deox}}}} & {{Eq}.\mspace{14mu} 43} \\{A_{940} = {A_{940{oxy}} + A_{940{deox}}}} & {{Eq}.\mspace{14mu} 44} \\{{Furthermore},} & \; \\{A_{oxy} = {A_{660{oxy}} + A_{940{oxy}}}} & {{Eq}.\mspace{14mu} 45} \\{A_{deox} = {A_{660{deox}} + A_{940{deox}}}} & {{Eq}.\mspace{14mu} 46} \\{and} & \; \\{A_{oxy} = {{E_{660{oxy}}*C_{oxy}*L} + {E_{940{oxy}}*C_{oxy}*L}}} & {{Eq}.\mspace{14mu} 47} \\{A_{deox} = {{E_{660{deox}}*C_{deox}*L} + {E_{940{deox}}*C_{deox}*L}}} & {{Eq}.\mspace{14mu} 48} \\{{Thus}\text{:}} & \; \\{\frac{A_{660{oxy}}}{A_{660{deox}}} = \frac{E_{660{oxy}}*C_{oxy}*L}{E_{660{deox}}*C_{deox}*L}} & {{Eq}.\mspace{14mu} 49}\end{matrix}$

Since the ratios of C_(oxy):C_(deox) are known, the equations can bewritten (canceling L in the process):

$\begin{matrix}{\frac{A_{660{deoxy}}}{A_{660{deox}}} = {\frac{E_{660{oxy}}*C_{tot}*S}{E_{660{deox}}*C_{tot}*\left( {1 - S} \right)} = \frac{E_{660{oxy}}*S}{E_{660{deox}}*\left( {1 - S} \right)}}} & {{Eq}.\mspace{14mu} 50}\end{matrix}$

Knowing saturation S and the extinction coefficients, permits the ratio,defined as R₆₆₀, to be solved. Returning to the absorbance equationsA_(660oxy) and A_(660deox):

A _(660oxy) =A ₆₆₀ *[R ₆₆₀/(1+R ₆₆₀)]

A _(660deox) =A ₆₆₀ −A _(660oxy)

The process can be repeated for the 940 nm absorbance, A₉₄₀. In summary,each of the individual absorbances, i.e., A_(660oxy), A_(660deox),A_(940oxy), A_(940deox) has been determined. Combining them as aboveprovides: A_(oxy), A_(deox), which can be rewritten:

A _(oxy) =C _(oxy) *L*(E _(660oxy) +E _(940oxy))  Eq. 51

A _(deox) =C _(deox) *L*(E _(660deox) +E _(940deox))  Eq. 52

At this point it is convenient to divide out the known extinctioncoefficient values to get A′_(oxy) and A′_(deox), which remain knownvalues:

A′ _(oxy) =C _(oxy) *L  Eq. 53

A′ _(deox) =C _(deox) *L  Eq. 54

As above, these equations can be manipulated with multiplication andlogarithms. Multiplying first:

A′ _(oxy) *A′ _(deox) =C _(oxy) *L*C _(deox) *L=C _(oxy) *C _(deox) *L²  Eq. 55

Then taking the logarithm:

log(A′ _(oxy) *A′ _(deox))=log(C _(oxy))+log(C _(deox))+2 log(L)  Eq. 56

This can be rewritten as:

log(C _(oxy))+log(C _(deox))=log(A′ _(oxy) *A′ _(deox))−2 log(L)  Eq. 57

The operations can now be performed in reverse order. Taking thelogarithms first:

log(A′ _(oxy))=log(C _(oxy))+log(L)  Eq. 58

log(A′ _(deox))=log(C _(deox))+log(L)  Eq. 59

Now multiplying these terms:

log(A′ _(oxy))*log(A′ _(deox))=[log(C _(oxy))+log(L)]*[log(C_(deox))+log(L)]=log(C _(oxy))*log(C _(deox))+log(L)*[log(C_(oxy))+log(C _(deox))]+log²(L)  Eq. 60

Now substituting for log(C_(oxy))+log(C_(deox)) from Equation 57 intoEquation 60:

log(A′ _(oxy))*log(A′ _(deox))=log(C _(oxy))*log(C _(deox))+log(L)*[

log(A′ _(oxy) *A′ _(deox))−2 log(L)]+log²(L)  Eq. 61

Rearranging this equation provides:

$\begin{matrix}\begin{matrix}{{{\log \left( A_{oxy}^{\prime} \right)}*{\log \left( A_{deox}^{\prime} \right)}} = {{{\log \left( C_{oxy} \right)}*{\log \left( C_{deox} \right)}} + {{\log (L)}*}}} \\{{{\log \left( {A_{oxy}^{\prime}*A_{deox}^{\prime}} \right)} - {{\log (L)}*}}} \\{{{2{\log (L)}} + {\log^{2}(L)}}} \\{= {{{\log \left( C_{oxy} \right)}*{\log \left( C_{deox} \right)}} + {{\log (L)}*}}} \\{{{\log \left( {A_{oxy}^{\prime}*A_{deox}^{\prime}} \right)} - {2{\log^{2}(L)}} +}} \\{{\log^{2}(L)}} \\{= {{{\log \left( C_{oxy} \right)}*{\log \left( C_{deox} \right)}} + {{\log (L)}*}}} \\{{{\log \left( {A_{oxy}^{\prime}*A_{deox}^{\prime}} \right)} - {\log^{2}(L)}}}\end{matrix} & {{Eq}.\mspace{14mu} 62}\end{matrix}$

Taking absorbance measurements at a different saturation gives differentvalues for A′_(oxy) and A′_(deox), as well as C_(oxy) and C_(deox). Asabove, once absorbance values for a given saturation are known, they areknown for all possible saturations.

Therefore, A′_(oxy) and A′_(deox) can be calculated for a differentsaturation, and performing the multiplication and logarithmmanipulations will generate a new equation. The original values ofA′_(oxy) and A′_(deox) are specified as A_(oxy1) and A_(deox1), and thenew values, A_(oxy2) and A_(deox2).

The equations thus become:

log(A _(oxy1))*log(A _(deox1))=log(C _(oxy1))*log(C_(deox1))+log(L)*log(A _(oxy1) *A _(deox1))−log²(L)  Eq. 63

log(A _(oxy2))*log(A _(deox2))=log(C _(oxy2))*log(C_(deox2))+log(L)*log(A _(oxy2) *A _(deox2))−log²(L)  Eq. 64

Since the term log²(L) occurs in both equations, it will be eliminatedby subtracting the equations from each other. Thus, subtracting Equation64 from Equation 63 provides:

$\begin{matrix}{{{{\log \left( A_{{oxy}\; 1} \right)}*{\log \left( A_{{deox}\; 1} \right)}} - {{\log \left( A_{{oxy}\; 2} \right)}*{\log \left( A_{{deox}\; 2} \right)}}} = {{{\log \left( C_{{oxy}\; 1} \right)}*{\log \left( C_{{deox}\; 1} \right)}} + {{\log (L)}*{\log \left( {A_{{oxy}\; 1}*A_{{deox}\; 1}} \right)}} - {\log^{2}(L)} - {\quad\left\lbrack {{{{\log \left( C_{{oxy}\; 2} \right)}*{\log \left( C_{{deox}\; 2} \right)}} + {{\log (L)}*{\log \left( {A_{{oxy}\; 2}*A_{{deox}\; 2}} \right)}} - {\log^{2}(L)}} = {{{\log \left( C_{{oxy}\; 1} \right)}*{\log \left( C_{{deox}\; 1} \right)}} - {\log\left( {{C_{{{oxy}\; 2}\;)}*{\log \left( C_{{deox}\; 2} \right)}} + {{\log (L)}*{\log \left( {A_{{oxy}\; 1}*A_{{deox}\; 1}} \right)}} - {{\log (L)}*{\log \left( {A_{{oxy}\; 2}*A_{{deox}\; 2}} \right)}}} \right.}}} \right.}}} & {{Eq}.\mspace{14mu} 65} \\{{\mspace{79mu} {= {{\log \left( C_{oxy1} \right)*{\log \left( C_{deox1} \right)}} - {{\log \left( C_{oxy2} \right)}*{\log \left( C_{deox2} \right)}} + {\log (L)}}}}*\left\lbrack {{\log \left( {A_{{oxy}\; 1}*A_{{deox}\; 1}} \right)} - {\log \left( {A_{{oxy}\; 2}*A_{{deox}\; 2}} \right)}} \right\rbrack} & {{Eq}.\mspace{14mu} 66}\end{matrix}$

Referring to Eq. 66, it can be seen that the log(L) term could beeliminated according to the invention, by forming new equations with 2different saturations and repeating the process. Again, any number ofequations at different saturations can be formed, and all will bedifferent.

Using reference numerals 3 and 4 to denote these new relationships,provides:

$\begin{matrix}{{{{\log \left( A_{{oxy}\; 3} \right)}*{\log \left( A_{{deox}\; 3} \right)}} - {{\log \left( A_{{oxy}\; 4} \right)}*{\log \left( A_{{deox}\; 4} \right)}}} = {{{\log \left( C_{{oxy}\; 3} \right)}*{\log \left( C_{{{deox}\; 3}\;} \right)}} - {{\log \left( C_{{oxy}\; 4} \right)}*{\log \left( C_{{deox}\; 4} \right)}} + {{\log (L)}*\left\lbrack {{\log \left( {A_{{oxy}\; 3}*A_{{deox}\; 3}} \right)} - {\log \left( {A_{{oxy}\; 4}*A_{{deox}\; 4}} \right)}} \right\rbrack}}} & {{Eq}.\mspace{14mu} 67}\end{matrix}$

To subtract Equation 67 from Equation 66, the coefficients of the log(L)terms must be equal, so Equation 67 can be multiplied by the following:

[log(A_(oxy1)*A_(deox1))−log(A_(oxy2)*A_(deox2)]/[log(A_(oxy3)*A_(deox3))−log(A_(oxy4)*A_(deox4))]

To simplify, representing by values of constants that are known oralready measured or determined:

$\begin{matrix}{k_{12} = {{{\log \left( A_{{oxy}\; 1} \right)}*{\log \left( A_{{deox}\; 1} \right)}} - {{\log \left( A_{{{oxy}\; 2}\;} \right)}*{\log \left( A_{{deox}\; 2} \right)}}}} & {{Eq}.\mspace{14mu} 68} \\{k_{34} = {{{\log \left( A_{{oxy}\; 3} \right)}*{\log \left( A_{{deox}\; 3} \right)}} - {{\log \left( A_{{oxy}\; 4} \right)}*{\log \left( A_{{deox}\; 4} \right)}k_{m}}}} & {{Eq}.\mspace{14mu} 69} \\{= {\left\lbrack {{\log \left( {A_{{oxy}\; 1}*A_{{deox}\; 1}} \right)} - {\log \left( {A_{{oxy}\; 2}*A_{{deox}\; 2}} \right)}} \right\rbrack/{\quad\left\lbrack {{\log\left( {A_{{oxy}\; 3}*A_{{deox}\; 3}} \right)} - {\log \left( {A_{{oxy}\; 4}*A_{{deox}\; 4}} \right)}} \right\rbrack \mspace{14mu}}}} & {{Eq}.\mspace{14mu} 70}\end{matrix}$

A further equation is formed by multiplying Equation 67 by k_(m). Thisensures that the log(L) terms are equal. Subtracting this new equationfrom Equation 66 eliminates the log(L) term:

k ₁₂−(k _(m) *k ₃₄)=log(C _(oxy1))*log(C _(deox1))−log(C _(oxy2))*log(C_(deox2))−km*[log(C _(oxy3))*log(C _(deox3))−log(C _(oxy4))*log(C_(deox4))]  Eq. 71

At this point, the equation has a constant on one side, and 4 terms inlog²C on the other. Equations at 4 values of saturation have been used,but these saturation values are all known. Thus:

C _(oxy1) =C _(tot) *S ₁  Eq. 72

C _(deox1) =C _(tot)*(1−S ₁)  Eq. 73

C _(oxy2) =C _(tot) *S ₂  Eq. 74

C _(deox2) =C _(tot)*(1−S ₂)  Eq. 75

C _(oxy3) =C _(tot) *S ₃  Eq. 76

C _(deox3) =C _(tot)*(1−S ₃)  Eq. 77

C _(oxy4) =C _(tot) *S ₄  Eq. 78

C _(deox4) =C _(tot)*(1−S ₄)  Eq. 79

The equation now becomes:

$\begin{matrix}{{k_{12} - \left( {k_{m}*k_{34}} \right)} = {{{\log \left( {C_{tot}*S_{1}} \right)}*{\log \left( {C_{tot}*\left( {1 - S_{1}} \right)} \right)}} - {{\log \left( {C_{tot}*S_{2}} \right)}*{\log \left( {C_{tot}*\left( {1 - S_{2}} \right)} \right)}} - {k_{m}*{\log \left( {C_{tot}*S_{3}} \right)}*{\log \left( {C_{tot}*\left( {1 - S_{3}} \right)} \right)}} + {k_{m}*{\log \left( {C_{tot}*S_{4}} \right)}*{\log \left( {C_{tot}*\left( {1 - S_{4}} \right)} \right)}}}} & {{Eq}.\mspace{14mu} 80}\end{matrix}$

Inspecting the 4 terms on the right hand side of this equationindividually:

$\begin{matrix}{{\left. {{{\log \left( {C_{tot}*S_{1}} \right)}*{\log \left( {C_{tot}*\left( {1 - S_{1}} \right)} \right)}} = {{\left\lbrack {{\log \left( C_{tot} \right)} + {\log \left( S_{1} \right)}} \right\rbrack*\left\lbrack {{\log \left( C_{tot} \right)} + {\log \left( {1 - S_{1}} \right)}} \right\rbrack} = {{\log^{2}\left( C_{tot} \right)} + {{\log \left( C_{tot} \right)}*{\log \left( S_{1} \right)}} + {{\log \left( C_{tot} \right)}*{\log \left( {1 - S_{1}} \right)}}}}} \right\rbrack + {{\log \left( S_{1} \right)}*{\log \left( {1 - S_{1}} \right)}}} = {{\log^{2}\left( C_{tot} \right)} + {{\log \left( C_{tot} \right)}*\left\lbrack {{\log \left( S_{1} \right)} + {\log \left( {1 - S_{1}} \right)}} \right\rbrack} + {{\log \left( S_{1} \right)}*{\log \left( {1 - S_{1}} \right)}}}} & {{Eq}.\mspace{14mu} 81}\end{matrix}$

Note that the log² term has 1 as coefficient. Since there are 4symmetrical terms, 2 adding and 2 subtracting, the log² terms willcancel out i.e.,

$\begin{matrix}{{k_{12} - \left( {k_{m}*k_{34}} \right)} = {{{\log \left( C_{tot} \right)}*\left\lbrack {{\log \left( S_{1} \right)} + {\log \left( {1 - S_{1}} \right)}} \right\rbrack} + {{\log \left( S_{1} \right)}*{\log \left( {1 - S_{1}} \right)}} - {{\log \left( C_{tot} \right)}*\left\lbrack {{\log \left( S_{2} \right)} + {\log \left( {1 - S_{2}} \right)}} \right\rbrack} - {{\log \left( S_{2} \right)}*{\log \left( {1 - S_{2}} \right)}} - {k_{m}*\left\lbrack {{{\log \left( C_{tot} \right)}*\left\lbrack {{\log \left( S_{3} \right)} + {\log \left( {1 - S_{3}} \right)}} \right\rbrack} + {{\log \left( S_{3} \right)}*{\log \left( {1 - S_{3}} \right)}}} \right\rbrack} + {k_{m}*\left\lbrack {{{\log \left( C_{tot} \right)}*\left\lbrack {{\log \left( S_{4} \right)} + {\log \left( {1 - S_{4}} \right)}} \right\rbrack} + {{\log \left( S_{4} \right)}*{\log \left( {1 - S_{4}} \right)}}} \right\rbrack}}} & {{Eq}.\mspace{14mu} 82}\end{matrix}$

All terms containing only log(S) or log(1−S) are known, so they can becollected and replaced with k_(s). Further, collecting all terms withC_(tot) provides:

$\begin{matrix}{\left. {{k_{12} - \left( {k_{m}*k_{34}} \right)} = {{{\log \left( C_{tot} \right)}*\left\lbrack {\left\lbrack {{\log \left( S_{1} \right)} + {\log \left( {1 - S_{1}} \right)}} \right\rbrack - {\log \left( S_{2} \right)} + {\log \left( {1 - S_{2}} \right)}} \right\rbrack} - {k_{m}*\left\lbrack {{\log \left( S_{3} \right)}{+ \log}\left( {1 - S_{3}} \right)} \right\rbrack} + {k_{m}*\left\lbrack {{\log \left( S_{4} \right)} + {\log \left( {1 - S_{4}} \right)}} \right\rbrack}}} \right\rbrack + k_{s}} & {{Eq}.\mspace{14mu} 83}\end{matrix}$

Again, all terms with log(S) or log(1−S) are known, so they can becollected and replaced with k_(cs). Note that k_(cs) cannot be zero, asthe saturations are all different. The equation thus becomes:

k ₁₂−(k _(m) *k ₃₄)=log(C _(tot))*k _(cs) +k _(s)  Eq. 84

where:

k ₁₂−(k _(m) *k ₃₄)−k _(s)=log(C _(tot))*k _(cs),

log(C _(tot))=[(k ₁₂−(k _(m) *k ₃₄)−k _(s) ]/k _(cs)

C _(tot)=antilog{[k ₁₂−(k _(m) *k ₃₄)−k _(s) ]/k _(cs)}

In summary, C_(tot), the concentration of hemoglobin, has beendetermined based entirely on known or measured values. It will beappreciated that, while this analysis assumes only 2 species ofhemoglobin, the determinations can be made with additional speciespresent by utilizing additional wavelengths of light.

If the saturation is known, the determination can be made using a singleabsorbance measurement from a single wavelength of light. Forillustration, absorbance employing a wavelength of 660 nm is detailedbelow.

$\begin{matrix}{{A_{660} = {A_{660{oxy}} + A_{660{deox}}}}{A_{660} = {{E_{660{oxy}}*C_{oxy}*L} + {E_{660{deox}}*C_{oxy}*L}}}{\frac{A_{660{oxy}}}{A_{660{deox}}} = \frac{E_{660{oxy}}*C_{oxy}*L}{E_{660{deox}}*C_{deox}*L}}} & {{Eq}.\mspace{14mu} 85}\end{matrix}$

Rewriting this equation to incorporate the known saturation S gives:

$\begin{matrix}{\frac{A_{660{oxy}}}{A_{660{deox}}} = {\frac{E_{660{oxy}}*C_{tot}*S}{E_{660{deox}}*C_{tot}*\left( {1 - S} \right)} = \frac{E_{660{oxy}}*S}{E_{660{deox}}*\left( {1 - S} \right)}}} & {{Eq}.\mspace{14mu} 86}\end{matrix}$

As above, this equation can be solved, providing the ratio R₆₆₀.Returning and solving for the actual absorbances A_(660oxy) andA_(660deox) provides:

A _(660oxy) =A ₆₆₀ *[R ₆₆₀/(1+R ₆₆₀)]

A _(660deox) =A ₆₆₀ −A _(660oxy)  Eq. 87

Finally, dividing out the known extinction coefficient values providesA′_(660oxy) and A_(660deox):

A′ _(660oxy) =C _(oxy) *L  Eq. 88

A′ _(660deox) =C _(deox) *L  Eq. 89

At this point, the same algorithm as above will work for the singlewavelength, allowing the substitution of the 660 nm absorbances for thetotal absorbances. That is, substituting A′_(660oxy) for A′_(oxy), etc.It will also be appreciated that performing analysis by both methods(manipulating C or manipulating L) independently can be used to verifyresults obtained by either technique.

An alternative measurement method utilizing venous absorbance follows.The technique is equally suitable for arterial measurements. Two probes,such as shown in FIG. 8, are placed on two separate digits. These probesshould be of fixed or at least known dimensions. The probes can be onone hand or both hands, as in FIG. 9. Raising the hand well above theheart causes the venous absorbance signal to fall to near zero, asheight of the probes will cause the pressure in the venous system withinthe probes to be below the CVP. Slowly lowering the digits will causethe veins to no longer be collapsed at some point. While this shouldhappen at the same point for both probes, it is not essential to thetechnique. As the lowering of the digits continues, the volume andpressure will rise above zero, and will continue rising as the digitsare lowered. The important concept is that the absorbances will not bethe same in both probes. Two dissimilar fingers, such as a thumb andfifth finger can be chosen, but in any case absorbances will not beidentical even between similar fingers. Circuitry such as that shown inFIG. 13, may be used to facilitate the measurements.

Since the dimensions of the probes are known, the concentration C of theblood within the probes can be imputed. Of course, this C will be muchhigher than the true concentration since the space within the probes isoccupied by other tissue and only a small part is blood. If H representsthe hydrostatic distance that the probes have moved since the beginningof venous absorbance (this is convenient to establish a zero point for agraph), then a graph of H vs. C will be different for the two probes, asthe amount of absorbing blood within the two probes is different. Giventhat the true concentration of hemoglobin in the blood is the samethroughout the vascular system, there is a further distance D (afraction of H) that a first probe with the lower concentration wouldhave to be physically lowered in order to achieve the same concentrationas the second probe.

Preferably, the dimensions of the probes should be minimized to increasethe accuracy of the concentration estimates, since the path length ofthe probes is much greater than the path length of blood. For example,halving the diameter of the probes doubles the measured concentration.

Since the true path length of non-scattering blood absorbance is verysmall, the point where H and (H+D) are in the same ratio as the imputedconcentrations yields the true concentrations. That is, if theconcentration ratios are 1:2 (twice as much absorbance in one probe),the true concentrations would be where H and D are equal. The actualconcentration of hemoglobin is that at point (H,C). The further length Drepresents the additional non-blood path length through the other probe.Note that this C occurs at only one point. Also note that H is not thetrue path length, but C is in fact the true concentration.

Advantageously, this technique can be repeated many times for one armmovement, can be used for both arterial and venous measurements, andarterial and venous measurements can be done simultaneously, and checkedagainst each other.

In another embodiment of the invention, hemoglobin concentration can bederived by taking ratios of absorbance at different pressures. Pressureis equal to dynes divided by the square of the path length, i.e.,

P=D/L ²  Eq. 90

and, as indicated above, Beer's Law is:

A=E*C*L  Eq. 91

Multiplying P by A² provides:

E²*C²*D  Eq. 92

Successive measurements give E²*C²*D₁, E²*C²*D₂, . . . E²*C²*D_(x) fromwhich ratios can be formed. Next, the values P+A² and P⁻¹+A² are knownquantities, and substituting Beer's Law and the pressure to lengthrelationship allows the latter to be written as:

L²/D²+E²*C²*L²  Eq. 93

Dividing by L² provides:

L²*(D⁻²+E²*C²)  Eq. 94

As before, successive measurements gives values L₁ ²*(D₁ ⁻²+E²*C²), L₂²*(D₂ ⁻²+E²*C²), . . . L_(x) ²*(D_(x) ⁻²+E²*C²). Since the path lengthratios are known, the values can be divided by L and the successivevalues can be divided to give the ratio:

(D ₁ ⁻² +E ² *C ²)/(D ₂ ⁻² +E ² *C ²)=m  Eq. 95

Further, D₁ ⁻²/D₂ ⁻² can be expressed in terms of D₂/D₁, which, asdiscussed above, is a known ratio. As E²*C² is a constant, equation 95is taking a known ratio, adding a constant to the numerator anddenominator, and arriving at another known ratio. Thus, the value of theconstant can be determined uniquely and precisely. As E is known, thisallows determination of C, the concentration of hemoglobin. Once C isdetermined, A=ECL allows computation of L, the path length anddetermination of L allows the computation of D as validation.

(D-5). Determination of pH and Acid-Base Balance

This probes and methods of this invention allow the pH and acid-basebalance of a patient's blood to be determined noninvasively,continuously and in real time. Generally, a probe such as thosedescribed above, containing one or more sources of emitted light isused, for example as shown in FIGS. 5 and 8. Preferably, the inventionutilizes light in the visible and near-infrared spectra, but otherwavelengths could be successfully used. Detection of transmitted lightis made by a photodetector. Suitable circuitry is shown in FIGS. 11 and14, for example. Determination of absorbance of the emitted light isdone using Beer's law. The emission, detection, and determination ofabsorbance described are all similar to that used in pulse oximeters,common in modern hospital settings. Using either pulse oximetry(filtering out all non-pulsatile signal components) or conventionalspectrophotometry, identification of methemoglobin, oxyhemoglobin,deoxyhemoglobin, and carboxyhemoglobin, species of human hemoglobin, ismade by utilizing known absorbance spectrums, such as those shown inFIG. 34.

The absorbance spectra of oxyhemoglobin, deoxyhemoglobin, andcarboxyhemoglobin, the more common hemoglobin species, areconventionally understood to be essentially unaffected by acid-basebalance over the most commonly used spectrophotometric range of 650-1000nm. However, all proteins and organic molecules are affected by pH tosome extent. FIG. 35 shows the absorption spectrum of hemoglobin A(deoxyhemoglobin) between 500 and 650 nm for 4 different pH values—pH 6,7, 8, and 9. It can be clearly seen that pH does have a significanteffect on the absorption spectrum. Thus, the spectrum of hemoglobinspecies is in fact altered by pH in the clinical range. The changes aresmall, and have largely been ignored by the prior art because they aretoo small to be considered clinically important for oxygen saturationmeasurements.

While many wavelengths may be affected, specific alterations have beenfound at wavelengths 535, 577, and 600 nm. For example, oxyhemoglobinshows absorption peaks at 535 and 577 nm that are greater at higher pH,while the trough near 600 nm is slightly deeper as illustrated in FIG.36. The upper panel is a difference spectrum magnified 10-fold to moreclearly illustrate the absorption pattern. The total hemoglobinconcentration in both curves was normalized arbitrarily at a wavelengthof 506 nm. It is estimated that this produces a difference in calculatedsaturation of about 3% from pH 7.6 to pH 6.8. Thus, saturationmeasurements accurate to 0.1% should define pH to within 0.05 pH units.

Ratiometric techniques similar to pulse oximetry can be used to exploitthese spectral differences in order to determine pH of the blood. As pHhas relatively little effect at the near infrared wavelengths,performing pulse oximetry using two wavelengths such as 660 and 940 canbe used to determine the “true” oxygen saturation of the blood (for now,assuming only the two species oxyhemoglobin and deoxyhemoglobin). Anadditional simultaneous measurement of at least one other wavelength—oneknown to be affected by pH, for example 535 or 577 nm—is performed. Bymaking pair-wise comparisons of the ratios at all the wavelengths, thepH can be measured from the saturation values. Preferably, amulti-wavelength spectrophotometer allows multiple comparisons.

Similarly, there are small pH-dependent changes in the absorptionspectra of carboxyhemoglobin and fetal hemoglobin. A pH effect has beendetermined on the carboxyhemoglobin (COHb) absorption spectrum. There isa bias of about 3% COHb per pH unit if pH is not taken into account.FIG. 37 illustrates an absorption spectrum and shows that the absorptionpeaks at 535 and 577 nm are higher, and the trough near 600 nm isslightly lower, at the higher pH value. Thus, the use of ratiometricdeterminations of predicted versus actual fraction of carboxyhemoglobincan be used to calculate pH of blood noninvasively using oximetrictechniques. Differences have been found in the absorption spectra ofspecies of fetal hemoglobin due to pH, especially fetalcarboxyhemoglobin. This is illustrated in FIGS. 31 and 32. Accordingly,noninvasive pH determinations can be made from its absorption ratios.

As mentioned above, the absorbance spectra of oxyhemoglobin,deoxyhemoglobin, and carboxyhemoglobin, the more common hemoglobinspecies, are affected relatively little by acid-base balance. Anotherembodiment of the invention exploits the optical spectrum ofmethemoglobin, which is very sensitive to pH in the physiologic range.Specifically, at pH 7 and below, the spectrum of aquomethemoglobin withmaximum at wavelength 630 nm is observed. At alkaline pH, the spectrumof hydroxymethemoglobin with disappearance of the maximum at 630 nm isseen. In terms of electron paramagnetic resonance spectra reflecting theelectronic spin state of the iron atom, in aquomethemoglobin the ironatom has a “high spin” state and is strongly paramagnetic. Withincreasing pH and the formation of hydroxymethemoglobin, the iron atomgoes to a low spin state, accompanied by a decrease in atomic radius.Since methemoglobin exists as an equilibrium mixture of structures, therelative amount of each can be used to determine the pH of the medium,blood.

Referring now to Table I, there is shown a table by which the extinctioncoefficients for methemoglobin for selected wavelengths of light can bedetermined, since the absorbance varies with the acid-base balance ofthe blood.

TABLE I Wavelength Species 540 560 570 576 640 Oxyhemoglobin 1.53 0.9061.23 1.65 0.015 deoxyhemoglobin 1.08 1.34 1.16 1.01 0.115carboxyhemoglobin 1.44 1.22 1.51 1.13 0.023 pH Methemoglobin 6.2 0.6090.373 0.355 0.358 0.412 6.4 0.610 0.374 0.356 0.360 0.410 6.6 0.6130.379 0.365 0.370 0.409 6.8 0.623 0.389 0.380 0.385 0.406 7.0 0.6380.405 0.400 0.406 0.401 7.2 0.658 0.424 0.425 0.433 0.393 7.4 0.6820.450 0.455 0.465 0.380 7.6 0.710 0.481 0.492 0.507 0.360 7.8 0.7460.520 0.537 0.558 0.324 8.0 0.788 0.567 0.590 0.620 0.306 8.2 0.8350.616 0.647 0.682 0.280 8.4 0.882 0.665 0.703 0.745 0.254 8.6 0.9260.710 0.755 0.800 0.230 8.8 0.964 0.749 0.801 0.850 0.208

From the information in Table I, Tables IIA and IIB can be created,which gives the ratios of the extinction coefficients for methemoglobinat the various pH values. To determine the pH using Tables IIA and IIB,one first determines either the absorbance due to methemoglobin at eachwavelength of interest, or the percentage of methemoglobin compared toother hemoglobin species. These determinations can be done usingtechniques described elsewhere in this application, or in other works.Once this has been done, the ratio of absorbances at the differentwavelengths can be used to compute the pH.

For example, if the ratio of absorbance of methemoglobin for a 540 nmwavelength light source to the absorbance of methemoglobin for a 560wavelength light source is 1.633, the pH is 6.2. If the ratio is instead1.516, the pH is approximately 7.4. Similar calculations can be made forother wavelengths, and the results compared to ensure accuracy.

TABLE IIA Methemoglobin pH 540/560 540/570 540/576 540/640 560/570 6.21.633 1.715 1.701 1.478 1.051 6.4 1.631 1.713 1.694 1.488 1.051 6.61.617 1.679 1.657 1.499 1.038 6.8 1.602 1.639 1.618 1.534 1.024 7.01.575 1.595 1.571 1.591 1.013 7.2 1.552 1.548 1.520 1.674 0.998 7.41.516 1.499 1.467 1.795 0.989 7.6 1.476 1.443 1.400 1.972 0.978 7.81.435 1.389 1.337 2.302 0.968 8.0 1.390 1.336 1.271 2.575 0.961 8.21.356 1.291 1.224 2.982 0.952 8.4 1.326 1.255 1.184 3.472 0.946 8.61.304 1.226 1.158 4.026 0.940 8.8 1.287 1.203 1.134 4.635 0.935

TABLE IIB Methemoglobin pH 560/576 560/540 570/576 570/640 576/640 6.21.042 0.905 0.992 0.862 0.869 6.4 1.039 0.912 0.989 0.868 0.878 6.61.024 0.927 0.986 0.892 0.905 6.8 1.010 0.958 0.987 0.936 0.948 7.00.998 1.010 0.985 0.998 1.012 7.2 0.979 1.079 0.982 1.081 1.102 7.40.968 1.184 0.978 1.197 1.224 7.6 0.949 1.336 0.970 1.367 1.408 7.80.932 1.605 0.962 1.657 1.722 8.0 0.915 1.853 0.952 1.928 2.026 8.20.903 2.200 0.949 2.311 2.436 8.4 0.893 2.618 0.944 2.768 2.933 8.60.888 3.087 0.944 3.283 3.478 8.8 0.881 3.601 0.942 3.851 4.087

In these embodiments of the invention, it is not necessary to computethe actual concentration of any hemoglobin species. Indeed, merely theratio or relative amount compared to other species yields sufficientinformation to determine blood pH and acid-base balance. In general, theseparate identification of n species will require at least n differentwavelengths of light to be used. If desired, more than the minimumnumber of wavelengths may be used.

These embodiments of the invention can be supplemented by consideringthe effect of temperature on the pH of blood. Temperature not onlyaffects the hemoglobin oxygen dissociation curve, but has an independenteffect on pH. FIG. 38 is a graph of the normal hemoglobin-oxygendissociation curve (HODC). FIG. 39 shows the effect of temperature andpH on the HODC of FIG. 38. Thus, measurements of spectra can be taken atmore that one temperature (and thus more than one pH), improving theaccuracy of determinations. The Henderson-Hasselbach equation, describesthe dissolution of an acid in terms of pH, pK (dissolution ordissociation constant), and the concentrations of the acid and its saltor base. The solubility, λ of carbon dioxide (CO₂) istemperature-dependent and the pK for CO₂ also depends on temperature.Thus, for CO₂ the Henderson-Hasselbach equation becomes pH=pK+log([HCO₃⁻]/λPCO₂), or an alternate form can be used. The temperature dependenceof the pK for carbonic acid is shown in Tables IIIA-IIIE below.

TABLE IIIA Tem- pera- PH ture 7.6 7.59 7.58 7.57 7.56 7.55 7.54 7.53 406.07 6.0705 6.071 6.0715 6.072 6.0725 6.073 6.0735 39 6.07 6.0705 6.0716.0715 6.072 6.0725 6.073 6.0735 38 6.08 6.0805 6.081 6.0815 6.0826.0825 6.083 6.0835 37 6.08 6.0805 6.081 6.0815 6.082 6.0825 6.0836.0835 36 6.09 6.0905 6.091 6.0915 6.092 6.0925 6.093 6.0935 35 6.16.1005 6.101 6.1015 6.102 6.1025 6.103 6.1035 33 6.1 6.1005 6.101 6.10156.102 6.1025 6.103 6.1035 30 6.12 6.1205 6.121 6.1215 6.122 6.1225 6.1236.1235

TABLE IIIB PH Temperature 7.52 7.51 7.5 7.49 7.48 7.47 7.46 7.45 7.44 406.074 6.0745 6.075 6.0755 6.076 6.0765 6.077 6.0775 6.078 39 6.0746.0745 6.075 6.0755 6.076 6.0765 6.077 6.0775 6.078 38 6.084 6.08456.085 6.0855 6.086 6.0865 6.087 6.0875 6.088 37 6.084 6.0845 6.0856.0855 6.086 6.0865 6.087 6.0875 6.088 36 6.094 6.0945 6.095 6.09556.096 6.0965 6.097 6.0975 6.098 35 6.104 6.1045 6.105 6.1055 6.1066.1065 6.107 6.1075 6.108 33 6.104 6.1045 6.105 6.1055 6.106 6.10656.107 6.1075 6.108 30 6.124 6.1245 6.125 6.1255 6.126 6.1265 6.1276.1275 6.128

TABLE IIIC PH Temperature 7.43 7.42 7.41 7.4 7.39 7.38 7.37 7.36 7.35 406.0785 6.079 6.0795 6.08 6.0805 6.081 6.0815 6.082 6.0825 39 6.07856.079 6.0795 6.08 6.0805 6.081 6.0815 6.082 6.0825 38 6.0885 6.0896.0895 6.09 6.0905 6.091 6.0915 6.092 6.0925 37 6.0885 6.089 6.0895 6.096.0905 6.091 6.0915 6.092 6.0925 36 6.0985 6.099 6.0995 6.1 6.1005 6.1016.1015 6.102 6.1025 35 6.1085 6.109 6.1095 6.11 6.1105 6.111 6.11156.112 6.1125 33 6.1085 6.109 6.1095 6.11 6.1105 6.111 6.1115 6.1126.1125 30 6.1285 6.129 6.1295 6.13 6.1305 6.131 6.1315 6.132 6.1325

TABLE IIID PH Temperature 7.34 7.33 7.32 7.31 7.3 7.29 7.28 7.27 7.26 406.083 6.0835 6.084 6.0845 6.085 6.0855 6.086 6.0865 6.087 39 6.0836.0835 6.084 6.0845 6.085 6.0855 6.086 6.0865 6.087 38 6.093 6.09356.094 6.0945 6.095 6.0955 6.096 6.0965 6.097 37 6.093 6.0935 6.0946.0945 6.095 6.0955 6.096 6.0965 6.097 36 6.103 6.1035 6.104 6.10456.105 6.1055 6.106 6.1065 6.107 35 6.113 6.1135 6.114 6.1145 6.1156.1155 6.116 6.1165 6.117 33 6.113 6.1135 6.114 6.1145 6.115 6.11556.116 6.1165 6.117 30 6.133 6.1335 6.134 6.1345 6.135 6.1355 6.1366.1365 6.137

TABLE IIIE PH Temperature 7.25 7.24 7.23 7.22 7.21 7.2 40 6.0875 6.0886.0885 6.089 6.0895 6.09 39 6.0875 6.088 6.0885 6.089 6.0895 6.09 386.0975 6.098 6.0985 6.099 6.0995 6.1 37 6.0975 6.098 6.0985 6.099 6.09956.1 36 6.1075 6.108 6.1085 6.109 6.1095 6.11 35 6.1175 6.118 6.11856.119 6.1195 6.12 33 6.1175 6.118 6.1185 6.119 6.1195 6.12 30 6.11756.118 6.1185 6.119 6.1195 6.12

Since [TCO₂] is very close to the sum of [HCO₃ ⁻] and λPCO₂, [HCO₃⁻]=[TCO₂]−λPCO₂, then:

pH=pK+log(([TCO₂]−λPCO₂)/λPCO₂)  Eq. 96

The degree of shift of the HODC can be calculated by:

temperature factor=antilog{0.024*(37−temperature)}  Eq. 97

pH factor=antilog{0.48*(pH−7.40)}  Eq. 98

base excess factor=antilog{−0.0013*base excess}  Eq. 99

Calculation of blood oxygen content can be made as follows:

content(ml O₂/dl)=THb(g/dl)*502*1.38(ml O₂/g HbO₂)+0.003*PO₂  Eq. 100

Conversion of PO₂ to SO₂ (and of SO₂ to PO₂) is done using modificationsof Adair's equation or Kelman's computation:

$\begin{matrix}{{SO}_{2} = \left( {25*{\left( {{0.0257*{PO}_{2}} + {0.00075*{PO}_{2}^{2}} + {3*0.00000444*{PO}_{2}^{3}} + {4*0.00000255*{PO}_{2}^{4}}} \right)/\left( {1 + {0.0257*{PO}_{2}} + {0.00078*{PO}_{2}^{2}} + {0.00000444*{PO}_{2}^{3}} + {0.00000255*{PO}_{2}^{4}}} \right)}} \right)} & {{Eq}.\mspace{14mu} 101}\end{matrix}$

Calculation of base excess can be done by the following formula, orother known means:

base excess=(1−0.0143*Hb)*([HCO₃ ⁻]24)  Eq. 102

These calculations and conversions represent approximate values asunderstood by those of skill in the art and the invention is not limitedto them. As improved estimations become available, they may be used withthe methods of the invention. Accordingly, alterations of this algorithmwill be suggested to those skilled in the art, and are meant to beincluded within the scope and spirit of this application.

Alternatively, values for PCO₂ and bicarbonate can be computed withoutthe use of temperature perturbation if the pH is known at two or morevalues. For example, techniques described elsewhere in this applicationshow that we can perform simultaneous measurements for arterial andvenous blood. The two compartments have the same temperature butdifferent pH values, and this allows formation of theHenderson-Hasselbach formulation into two equations for two unknowns:PCO₂ and [HCO₃ ⁻].

(D-6). Determination of Temperature

The shifts in the HODC shown in FIG. 39 relative to the curve shown inFIG. 38 are caused primarily by two factors: pH and temperature. Thus,the pH of two samples of blood at the same temperature will define whichcurve the blood is at, and thus what the temperature of the blood is.The techniques described elsewhere in this application can be used toprovide simultaneous determinations of arterial and venous blood pHwithin a probe. As these pH values will be slightly different, the HODCcan be defined, and temperature calculated quite accurately. This methodof the invention gives a true, noninvasive measurement of bloodtemperature. Since the blood flow to the finger or other member withinthe probe is continuously refreshed, the measurement is a very accurateestimate of central or “core” temperature.

(D-7). Determination of Glucose Concentration

Most substances in blood are present in essentially the sameconcentration in arterial and venous blood. However, this is not truefor substances that are consumed in significant quantities in themetabolic process. The most prominent of these are oxygen and glucose.This is especially true when dealing with molar quantities, as inspectrophotometry. The technique for determining venous oxygensaturation has been described above. Once both arterial and venoussaturation are determined, their absorbances can be “normalized”. Thiscan also be performed for pH, as above.

A subtraction of hemoglobin absorbance may then be performed,effectively removing it. What remains is the absorbance due tonon-hemoglobin absorbers. This provides an estimation of glucoseconcentration since the largest non-hemoglobin absorber is glucose.Additionally, the absorbance at each wavelength can be compared forarterial and venous blood. A vast majority of the non-hemoglobinabsorbers, but not glucose, will be of the same concentration in botharterial and venous blood. By subtracting out the constant absorbancebetween arterial and venous blood, the remaining glucose absorbance canbe measured, and glucose concentration can be accurately determined.

(D-8). Determination of Chemical Analytes

Once the concentration of hemoglobin is known, the concentration of manysubstances in blood could be determined as ratios of the concentrationof hemoglobin. The use of multiple wavelengths will allowdifferentiation between molecules, and comparison can be made toconcentration of hemoglobin even without knowledge of path length. Afurther embodiment of the invention establishes standards by creatinglayers or films containing known amounts of analytes of interest. Thesecan then be compared optically with the changes due to blood volumeshifts within a probe. Such techniques are not possible withconventional pulse oximetry as the signal from the film would simply befiltered out with all other unchanging (DC) signal. This inventionovercomes this drawback by using venous measurements, and thus does notrequire limitation to pulsatile (AC) signal.

One exemplary method includes the steps of placing a film that containsa known concentration of an analyte within a probe system, such as oneconfigured for a finger. The absorbance of the finger plus film systemis measured for a given number of wavelengths of light. The blood volumeof the finger is changed by raising or lowering it with respect to theheart (as outlined elsewhere in this application). As it can be assumedthat the change in absorbance is due to change in blood volume, one cancompare blood absorbance to film absorbance, and hence relativeconcentration of the analyte in blood to that in the film. Sufficientwavelengths must be examined to provide specificity for the analyte inquestion, as there are many potential absorbers in blood.

(D-9). Determination of Congenital Heart Disease and Anatomic Anomalies

Diagnosis of many disorders with anatomic anomalies can be made by thedetection of unexpected propagation times, and abnormal propagationdelays between right- and left-sided organs. The ability to measure botharterial and venous saturation, as well as arterial and venouspressures, can aid further in investigations.

For example, coarctation of the aorta is a common congenitalabnormality. It is a narrowing or constriction of the thoracic aorta. Itcan occur before or after the origin of the left subclavian artery. Ineither case, the blood pressure will be much lower in the legs than thearms. Because of the constriction, both pressure and flow waves will begreatly delayed in the lower limbs as compared to the upper. If a childhas a coarctation proximal to the origin of the left subclavian artery,there will be a significant discrepancy in the pulse and flow wavearrival times of the two arms, with the right preceding the left.

(D-10). Determination of Dysrhythmias

By measuring blood pressure and the electrocardiogram simultaneously,the diagnosis of dysrhythmias can be aided greatly. Both arterial andvenous pressure are recorded simultaneously with the ECG, allowingdifferentiation of atrial vs. ventricular arrhythmias as well ascorrelation to Q-T interval.

It can be difficult to distinguish dysrhythmias of atrial conductionfrom those of ventricular conduction. However, these often manifest muchdifferent hemodynamic effects. Those with normal ventricular conductionand eject often maintain cardiac output and blood pressure closer tonormal.

(D-11). Determination of Additional Cardiovascular Parameters

By measuring blood pressure and the electrocardiogram simultaneously,many additional parameters, such as systolic and diastolic pressure timeindices, can be determined. An enormous amount of information can begleaned from the use of probes on opposite sides of the body combinedwith hydrostatic perturbations. The time of arrival of a pulse to pairedmembers is different, but the velocity of the pulse is also different.Examination of pulse propagation time, pulse propagation phase or delay,pulse velocity, and pulse amplitude gives four parameters that maychange in different ways for each perturbation. Circuitry such as thatshown in FIG. 13, is suitable for use in such embodiments. In oneembodiment, raising and lowering an arm by the same amount may givedifferent changes. Raising and lowering the other arm by the same amountmay give still different changes. In an alternative embodiment, raisingan arm by a given amount, then raising again by the same amount, maygive different changes. Raising the other arm by the given amount, thenraising again by the same amount, may give still different changes.Similarly measurement can be taken for lowering.

(D-12). Determination of Aortic Pressure

Using the methods and probes of the invention allows the aortic pressureto be determine and the reconstruction of the aortic pressure curve.This can be accomplished through fluid mechanics or changing thereflection wave from the lower extremities. Details of exemplarytechniques may be found in U.S. Pat. Nos. 5,265,011, 5,882,311, and6,010,457 which are hereby incorporated by reference thereto.

(D-13). Determination of Carotid Stenosis

The carotids are paired arteries running from the chest through the neckto the head, and provide the major source of blood supply to the headand brain. As they have different origins, they have different pathlengths for pulse transmission and blood flow from the heart. Asignificant discrepancy in pulse and flow wave velocity in one carotidartery as compared to the other, or in paired arteries arising from thecarotids (such as the facial arteries) suggest a stenosis on the sideexhibiting the delay.

(D-14). Determination of Peripheral Vascular Disease

Peripheral vascular disease results in narrowing of the lumen ofperipheral arteries, most commonly the large arteries of the leg.Because of this stenosis, the blood flow characteristics of the arteryaffected are altered, and thus the pulse and flow waves distal to theobstruction. If a probe is placed distal to the obstruction, significantdelays will be noted. Again, this is best done when compared to a pairedorgan; for example, placing probes on the great toes of both feet tocompare the wave characteristics of the arteries of the two legs.

(D-15). Determination of Compartment Syndrome

Compartment syndrome is hypoperfusion and resulting ischemia of a bodymember, commonly an arm or a leg, secondary to swelling caused by tissuedamage. If the swelling is significant, the increased volume of thetissue may increase the pressure in the limb (compartment) to such anextent that it cuts off the arterial blood supply. This can be monitoredby placing a probe distal to the compartment to measure the pulse andflow wave velocities. This is done preferably with a paired organ tocompare the two. Slowing of the pulse wave and increase in the arrivaltime signal diminishing blood pressure within the compartment, which caneventually result in ischemia and gangrene if steps are not taken torelieve the pressure, normally with surgery.

(D-16). Determination of Autonomic Activity, Sedation and Depth ofAnesthesia

There are normal variations in pulse baseline, pulse amplitude, andbeat-to-beat variability. These factors are thought to be indicative ofautonomic nervous activity or “tone”. All these factors can be measuredby the device and techniques of the invention. An alternative embodimentinvention can also be used as a monitor of autonomic activity, sedation,or “depth of anesthesia”.

(D-17). Determination of Heart Rate

According to the invention, heart rate can be determined by counting thepulsatile arterial signal for a known length of time, or by the ECGimpulse.

(D-18). Determination of Respiratory Rate

The impedance changes of the chest due to filling and emptying can bemeasured from the electrocardiogram tracing. During normal breathing,negative pressure is created within the chest by lowering of thediaphragm and expansion of the rib cage. This negative pressure causesblood to empty more rapidly from the peripheral into the central veins.This is also the case when respiration is assisted by anegative-pressure device such as the “iron lung”.

During modern mechanically-assisted ventilation (with “ventilators”),positive pressure is created within the chest by forcing air into thelungs. For both positive- and negative-pressure ventilation, expirationis passive. This respiratory variation by itself can be used as anestimate of cardiac filling, giving left heart pressures. Thisdetermination can be assisted by the use of the hydrostatic techniquesdescribed above.

(D-19). Determination of EEG and EMG

Just as leads capable of detecting and transmitting electrocardiogram(ECG) signals can be included in the probes (as outlines elsewhere inthis application), similar techniques will allow monitoring of theelectroencephalogram (EEG) and electromyogram (EMG).

(D-20). Determination of Cardiac Ejection Fraction

This determination is made based upon the rate of change of saturation.If blood in a container is of a stable, known saturation, and blood of adifferent saturation is added, the rate of change is dependent on twothings: the saturation of the blood being added, and the amount of bloodthat is flowing in (equivalent to blood flowing out). The stroke volumesof the right and left ventricles must be the same, so the inflow perheartbeat to the left ventricle must be the same as the outflow. Whilethe saturation of blood flowing from the lungs to the left heart may notbe precisely known, it will quickly equilibrate. This equilibrationprocess allows the determination of ejection fraction to be made.

The saturation of the blood in the left side of the heart, specificallythe left ventricle, is completely dependent on the oxygenation of theblood pumped into the lung by the right ventricle. The blood pumped bythe left ventricle into the arterial tree maintains its saturation untilit reaches the capillary beds of the organs. The blood returning to theright heart is a combination of widely varying saturations (due to thegreatly differing extractions of the various organs). However, the bloodpumped by the right ventricle equilibrates over the vast capillarynetwork of the lungs. Furthermore, any differences in saturation ofblood in the pulmonary venous system are thoroughly mixed in the leftatrium and left ventricle.

Breathing an oxygen-enriched gas mixture will change the alveolarconcentration of oxygen. A single deep breath after exhalation may bethe preferred method. While healthy subjects can inhale a vital capacity(VCII) breath of near total lung capacity (TLC), one cannot expect thisof all patients. However, it is not necessary to know the precise oxygenlevel in the lungs. All that is necessary is to induce a change insaturation. This works well for the determination, as it is much easierto produce saturation change in disease states, because the patientstarts farther away from the maximum value of 100%. Preferably, this maybe achieved through a breath-hold after the inspiration. Wash-out can beaccounted for (one knows that the inspired gas is air), however, thiscomplicates the otherwise simple mathematics. The breath holding isrequired for only several heartbeats, normally only a few seconds.

Even with holding one's breath, oxygen levels within the lung drop dueto absorption by blood. However, even with high hemoglobin levels, thenormal amount of oxygen carried by blood is about 20 cc/dL, and, asmixed venous saturation is normally about 75%, only about 5 cc/dL aretaken up. Given a cardiac stroke volume of 100 cc (higher than normal),this is only 5 cc per heartbeat. A small breath will provide enoughoxygen for several heartbeats, which should be all that is required.

Thus, an approximation is made that the concentration of oxygen in thelungs after oxygen inhalation is stable for several heartbeats. Thefirst heartbeat after the inhalation will result in blood of a changedsaturation entering the left heart from the lungs (may be 2nd heartbeat,accounting for “dead space” of the pulmonary veins). This will mix withthe blood remaining from the last cardiac ejection. This remaining bloodis the end-systolic volume of the left ventricle. It is theend-diastolic volume minus the stroke volume. The saturation of theblood in the left ventricle after mixing is between that of theend-systolic blood and the fresh blood from the lungs. The saturation ofthe mixed blood is measured after it is ejected to the periphery. Thearrival of the blood at the periphery can be judged by the change insaturation from the baseline measurement. The saturation rises dependingon the ratio of end-systolic blood to stroke volume. The higher thestroke volume, the faster the change in saturation. This can be lookedat as either a “wash in” or “wash out” function.

Thus, a high ejection fraction results in a rapid change in saturationas shown in FIG. 40. The rapid change is represented by the relativelysteep slope of the plot. In contrast, a low ejection fraction causes aslow change in saturation as shown in FIG. 41. Correspondingly, the slowchange is represented by a relatively shallow slope of the plot. Theexact same physiologic process reveals information about the cardiacoutput. As blood leaves the left ventricle, it travels to the aorta andthen to the periphery. Just as the pulse arrives at different points ofthe body at different times, so does the blood flow from a givenheartbeat. The blood travels much more slowly than the pulse wave, sothe time delays are much greater. The change in oxygen saturationproduces identifies the blood from individual beats to trace its arrivaltime to different parts of the body. By placing pulse oximeter probes atdifferent points of the body (a finger and a toe, for example) andcontinuously monitoring saturation, the saturation change produced bythe oxygen inhalation will occur in all parts of the arterial tree, butat different time intervals. The timing and ratio of these intervals isdetermined by the cardiac output—the longer the arrival time of thesaturation change (and the greater the interval between finger and toe),the lower the cardiac output. Conversely, the shorter the arrival timeof the saturation change (and the shorter the interval between fingerand toe), the higher the cardiac output. Note that it is not necessaryto maintain a breath-hold through the measurement since only a change insaturation is required.

An exemplary determination of cardiac ejection fraction starts withbaseline saturation and saturation increasing because of inhalation ofoxygen-rich gas:

Let dS be change in saturation S.

After 1 time constant, dS will have risen to approximately 63% of itsfinal value.

After 2 time constants, dS will have risen to approximately 86.5% of itsfinal value.

After 3 time constants, dS will have risen to approximately 95% of itsfinal value.

After 5 time constants, dS will have risen to approximately 99% of itsfinal value.

If the resting (“control”) saturation is 95%, and it rises to 99% afteroxygenation, total dS is 4.0%. Thus, 1 time constant is 0.63*4.0=2.52percent, for a saturation value of 95.0+2.5=97.5%.

2 time constants are 0.865*4.0=3.46 percent, for a saturation value of95.0+3.46=98.5%.

3 time constants are 0.95*4.0=3.80 percent, for a saturation value of95.0+3.=98.8%.

5 time constants are 0.99*4.0=3.96 percent, for a saturation value of95.0+2.=98.96%.

For this system, the time constant is the number of heartbeats that itwould take to fill the ventricle from the empty state, or empty theventricle from the full state. For example, an ejection fraction of 50%implies two heartbeats to fill or empty the ventricle, so the timeconstant is 2 beats. An EF of 80% implies a time constant of 1.25 beats,although this might be expressed more physiologically as 5 heartbeatsare 4 time constants. A “worst case” scenario of an EF around 20%corresponds to a time constant of 5 heartbeats. Clinically, some type ofcalibration may be required, as actual measurements may not correspondexactly to these theoretical values.

It is expected that a minimum of 2 time constants are required toproduce a satisfactory measurement, so an EF 20% would take 10 or moreheartbeats. However, there is the trade-off in that there are more beatsto analyze, so the curve can be fitted more precisely. Thus, it shouldbe possible in almost all cases to produce an accurate determinationwithin a few heartbeats after noting the saturation change.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. As such, thesechanges and modifications are properly, equitably, and intended to be,within the full range of equivalence of the following claims.

1-6. (canceled)
 7. A method for noninvasively determining physiologicparameters of a patient, comprising the steps of: providing a firsttissue probe, said first tissue probe including a first radiationemitter adapted to emit first radiation having a first wavelength and afirst radiation detector adapted to receive said first radiation afterabsorbance through a first radiation path length of the patient's blood;measuring absorbance of the patient's blood by transmitting said firstradiation at said first wavelength through the patient's blood anddetecting said first radiation after passage through the patient'sblood; providing a second tissue probe, said second tissue probeincluding a second radiation emitter adapted to emit second radiationhaving a second wavelength and a second radiation detector adapted toreceive said second radiation after absorbance through a secondradiation path length; measuring second absorbance of the patient'sblood at a second patient site by transmitting said second radiation atsaid second wavelength through the patient's blood and detecting saidsecond radiation after passage through the patient's blood; determiningfirst hemoglobin absorbance at said first patient site and secondhemoglobin absorbance at said second patient site; timing the arrival ofpulse and flow waves at the first and second patient sites by comparingsaid first and second hemoglobin absorbances; and determining a cardiaccharacteristic based on said arrival times of said pulse and flow waves.8-16. (canceled)
 17. A method for noninvasively determining physiologicparameters of a patient, comprising the steps of: providing a firsttissue probe, said first tissue probe including a first radiationemitter adapted to emit first radiation having a first wavelength and afirst radiation detector adapted to receive said first radiation afterabsorbance through a first radiation path length of the patient's blood;providing a second tissue probe, said second tissue probe including asecond radiation emitter adapted to emit second radiation having asecond wavelength and a second radiation detector adapted to receivesaid second radiation after absorbance through a second radiation pathlength; varying the volume and pressure of the patient's blood at firstand second patient sites, said first patient site being proximate saidfirst tissue probe, said second patient site being proximate secondtissue probe; measuring first absorbance of the patient's blood at saidfirst patient site as said blood volume and pressure are varied bytransmitting said first radiation at said first wavelength through thepatient's blood and detecting said first radiation after passage throughthe patient's blood; measuring second absorbance of the patient's bloodat said second patient site as said blood volume and pressure are variedby transmitting said second radiation at said second wavelength throughthe patient's blood and detecting said second radiation after passagethrough the patient's blood; timing the arrival of pulse and flow wavesat said first and second patient sites by comparing said first andsecond absorbances measured said first and second patient sites probe;and determining a cardiac characteristic based on said arrival times ofsaid pulse and flow waves.
 18. The method of claim 17, furthercomprising the step of using an electrocardiogram to correlate timing ofsaid first and second hemoglobin absorbance measurements. 19-29.(canceled)
 30. A method for non-invasively determining a cardiaccharacteristic of a patient, comprising the steps of: measuring pulsewave velocity in a first extremity; determining flow wave velocity; andcomputing the cardiac output characteristic using the flow wavevelocity.
 31. The method of claim 30, wherein said step of computing thecardiac characteristic comprises determining a characteristic selectedfrom the group comprising cardiac output, cardiac index, cardiac strokevolume, cardiac ejection fraction, and blood volume.
 32. The method ofclaim 30, further comprising the step of measuring pulse wave velocityin a second, opposite extremity and wherein the step of determining flowwave velocity comprises computing the flow wave velocity using theratios of the pulse wave velocities in said first and secondextremities.
 33. The method of claim 32, wherein the first and secondextremities comprise the patient's left and right hands.
 34. The methodof claim 32, wherein the steps of measuring pulse wave velocity comprisemeasuring the time intervals for arrival of pulses in said first andsecond extremities.
 35. The method of claim 30, further comprises thestep of measuring blood pressure and wherein the step of determiningflow wave velocity comprises computing the flow wave velocity using saidblood pressure and said pulse wave velocity.
 36. The method of claim 32,wherein the steps of measuring pulse wave velocity comprises the stepsof placing first and second tissue probes on different locations of thepatient's body, continuously monitoring oxygen saturation in thepatient's blood through said first and second tissue probes, inducing achange in oxygen saturation, and comparing the arrival time of thesaturation change at said first and second tissue probes.
 37. The methodof claim 36, wherein the step of inducing a change in oxygen saturationcomprises having the patient breath-hold.
 38. The method of claim 30,further comprising the step of inducing a change in oxygen saturation.39. The method of claim 38, wherein the cardiac characteristic isselected from the group comprising cardiac index, cardiac stroke volumeand cardiac output, and the cardiac characteristic is computed bydetermining the time interval between said inducement of change inoxygen saturation and a first measured change in oxygen saturation. 40.The method of claim 38, wherein the cardiac characteristic comprisescardiac ejection fraction and the cardiac characteristic is computed bydetermining the time interval between a first measured change in oxygensaturation and maximal change in oxygen saturation.
 41. The method ofclaim 38, wherein the cardiac characteristic comprises blood volume andthe cardiac characteristic is computed by determining the time intervalbetween said inducement of change in oxygen saturation and return to abaseline measured oxygen saturation.
 42. The method of claim 36, whereinthe step of inducing a change in oxygen saturation comprises providingan enriched oxygen atmosphere.
 43. A method for noninvasivelydetermining the blood pressure of a patient comprising the steps of:measuring the pulse wave velocity in a first extremity of the patient ata first pressure; inducing pressure change in the first extremity;measuring the pulse wave velocity in the first extremity at a secondpressure; and computing the blood pressure using ratios of said pulsewave velocities and the hydrostatic pressure difference of said firstand second pressures.
 44. The method of claim 43, wherein the step ofinducing a pressure change in said first extremity comprises varying theheight of said first extremity relative to the patient's heart.
 45. Themethod of claim 43, further comprising the step of measuring pulse wavevelocity in a second extremity.
 46. The method of claim 45, furthercomprising the step of inducing pressure change in said secondextremity.
 47. A method for noninvasively determining the blood pressureof a patient comprising the steps of: measuring a first time intervalfor a pulse to reach a first location in a first extremity at a firstpressure; inducing a pressure change in said first extremity by varyingthe height of the first extremity relative to the patient's heart;measuring a second time interval for a pulse to reach said firstlocation in said first extremity at a second pressure; and computing theblood pressure using the ratios of said first and second time intervalsand the hydrostatic pressure difference of said first and secondpressures. 48-49. (canceled)
 50. A method for noninvasively determininga patient's blood pressure, comprising the steps of: measuring pulsewave velocities in two opposite patient extremities; and computing theblood pressure using the ratios of said pulse wave velocities.
 51. Amethod for noninvasively determining the blood pressure, comprising thesteps of: measuring the time intervals for arrival of a pulse in twoopposite extremities; and computing the blood pressure using the ratiosof said two time intervals. 52-55. (canceled)